NEW OCTAHYDRO-PYRROLO[3,4-c]-PYRROLE DERIVATIVES AND ANALOGS THEREOF AS AUTOTAXIN INHIBITORS

ABSTRACT

The invention provides novel compounds having the general formula (I) 
     
       
         
         
             
             
         
       
     
     wherein R 1 , Y, A, W, R 2 , m, n, p and q are as described herein, compositions including the compounds and methods of using the compounds.

The present invention relates to organic compounds useful for therapy orprophylaxis in a mammal, and in particular to autotaxin (ATX) inhibitorswhich are inhibitors of lysophosphatidic acid (LPA) production and thusmodulators of LPA levels and associated signaling, for the treatment orprophylaxis of renal conditions, liver conditions, inflammatoryconditions, conditions of the nervous system, conditions of therespiratory system, vascular and cardiovascular conditions, fibroticdiseases, cancer, ocular conditions, metabolic conditions, cholestaticand other forms of chronic pruritus and acute and chronic organtransplant rejection.

The present invention provides novel compounds of formula (I)

-   -   wherein    -   R¹ is substituted cycloalkyl, substituted cycloalkylalkyl,        substituted phenyl, substituted phenylalkyl, substituted        phenoxyalkyl, substituted phenylcycloalkyl, substituted        phenylalkenyl, substituted phenylalkynyl, substituted naphthyl,        substituted naphthylalkyl, substituted naphthyloxyalkyl,        substituted naphthylalkenyl, substituted pyridinyl, substituted        pyridinylalkyl, substituted pyridinylalkenyl, substituted        pyridinylalkynyl, substituted thiophenyl, substituted        thiophenylalkyl, substituted thiophenylalkenyl, substituted        thiophenylalkynyl, substituted indolyl, substituted quinolyl,        substituted isoquinolyl, substituted        2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl or        substituted benzofuran-2-yl wherein substituted cycloalkyl,        substituted cycloalkylalkyl, substituted phenyl, substituted        phenylalkyl, substituted phenoxyalkyl, substituted        phenylcycloalkyl, substituted phenylalkenyl, substituted        phenylalkynyl, substituted naphthyl, substituted naphthylalkyl,        substituted naphthyloxyalkyl, substituted naphthylalkenyl,        substituted pyridinyl, substituted pyridinylalkyl, substituted        pyridinylalkenyl, substituted pyridinylalkynyl, substituted        thiophenyl, substituted thiophenylalkyl, substituted        thiophenylalkenyl, substituted thiophenylalkynyl, substituted        indolyl, substituted quinolyl, substituted isoquinolyl,        substituted 2,3-dihydro-1H-isoindol-2-yl, substituted        1H-indol-2-yl and substituted benzofuran-2-yl are substituted        with R⁷, R⁸ and R⁹;    -   R² is substituted phenyl, substituted pyridinyl, substituted        pyrrolyl, oxodihydropyridinyl or substituted thiophenyl, wherein        substituted phenyl, substituted pyridinyl, substituted pyrrolyl        and substituted thiophenyl are substituted with R¹⁰, R¹¹ and        R¹²;

-   -   Y is —OC(O)—, —NR⁵C(O)—, —C(O)—, —S(O)₂—,    -   A is —N— or CH—;    -   W is —O—, —S—, —NR⁶—, —C(O)—, —S(O)₂—, or —CR³R⁴—;    -   R³ and R⁴ are independently selected from H, halogen, alkyl and        cycloalkyl;    -   R⁵ and R⁶ are independently selected from H, alkyl and        cycloalkyl;    -   R⁷, R⁸ and R⁹ are independently selected from H, alkyl,        hydroxyalkyl, haloalkyl, hydroxyhaloalkyl, cycloalkyl,        cycloalkylalkyl, cycloalkylalkoxy, cycloalkoxy,        cycloalkoxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl,        haloalkoxy, alkoxyhaloalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl,        phenyl, substituted phenyl, pyridinyl, substituted pyridinyl,        halogen, hydroxy, cyano, alkylsulfanyl, haloalkylsulfanyl,        cycloalkylsulfanyl, alkylsulfinyl, haloalkylsulfinyl,        cycloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,        cycloalkylsulfonyl, substituted aminosulfonyl, substituted amino        and substituted aminoalkyl, wherein substituted aminosulfonyl,        substituted amino and substituted aminoalkyl are substituted on        the nitrogen atom with one to two substituents independently        selected from H, alkyl, cycloalkyl, cycloalkylalkyl,        hydroxyalkyl, alkoxyalkyl, alkylcarbonyl and cycloalkylcarbonyl,        and wherein substituted phenyl and substituted pyridinyl are        optionally substituted with one to three substituents        independently selected from alkyl, halogen, haloalkyl, alkoxy        and haloalkoxy, wherein at least one of R⁷, R⁸ and R⁹ is not H;    -   R¹⁰ is substituted aminosulfonyl, alkoxycarbonyl,        alkylcarbonylamino, alkylsulfonylamino, substituted amino,        carboxy, cyano, hydroxy or tetrazolyl, wherein substituted amino        is substituted on the nitrogen atom with one to two substituents        independently selected from H, alkyl, cycloalkyl,        cycloalkylalkyl, hydroxyalkyl and alkoxyalkyl;    -   R¹¹ and R¹² are independently selected from H, alkyl,        cycloalkyl, alkoxy, halogen and haloalkyl;    -   m, n, p and q are independently selected from 1 or 2;    -   or pharmaceutically acceptable salts.

Autotaxin (ATX) is a secreted enzyme also called ectonucleotidepyrophosphatase/phosphodiesterase 2 or lysophospholipase D that isimportant for converting lysophosphatidyl choline (LPC) to the bioactivesignaling molecule lysophosphatidic acid (LPA). It has been shown thatplasma LPA levels are well correlated with ATX activity and hence ATX isbelieved to be an important source of extracellular LPA. Earlyexperiments with a prototype ATX inhibitor have shown that such acompound is able to inhibit the LPA synthesizing activity in mouseplasma. Work conducted in the 1970s and early 1980s has demonstratedthat LPA can elicit a wide range of cellular responses; including smoothmuscle cell contraction, platelet activation, cell proliferation,chemotaxis and others. LPA mediates its effects via signaling to severalG protein coupled receptors (GPCRs); the first members were originallydenoted Edg (endothelial cell differentiation gene) receptors orventricular zone gene-1(vzg-1) but are now called LPA receptors. Theprototypic group now consists of LPA1/Edg-2NZG-1, LPA2/Edg-4, andLPA3/Edg-7. Recently, three additional LPA receptors LPA4/p2y9/GPR23,LPA5/GPR92 and LPA6/p2Y5 have been described that are more closelyrelated to nucleotide-selective purinergic receptors than to theprototypic LPA1-3 receptors. The ATX-LPA signaling axis is involved in alarge range of physiological and pathophysiological functions,including, for example, nervous system function, vascular development,cardiovascular physiology, reproduction, immune system function, chronicinflammation, tumor metastasis and progression, organ fibrosis as wellas obesity and/or other metabolic diseases such as diabetes mellitus.Therefore, increased activity of ATX and/or increased levels of LPA,altered LPA receptor expression and altered responses to LPA maycontribute to the initiation, progression and/or outcome of a number ofdifferent pathophysiological conditions related to the ATX/LPA axis.

In accordance with the invention, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis of diseases, disorders or conditions that areassociated with the activity of autotaxin and/or the biological activityof lysophosphatidic acid (LPA).

The compounds of formula (I) or their pharmaceutically acceptable saltsand esters herein inhibit autotaxin activity and therefore inhibit LPAproduction and modulate LPA levels and associated signaling. Autotaxininhibitors described herein are useful as agents for the treatment orprevention of diseases or conditions in which ATX activity and/or LPAsignaling participates, is involved in the etiology or pathology of thedisease, or is otherwise associated with at least one symptom of thedisease. The ATX-LPA axis has been implicated for example inangiogenesis, chronic inflammation, autoimmune diseases, fibroticdiseases, cancer and tumor metastasis and progression, ocularconditions, metabolic conditions such as obesity and/or diabetesmellitus, conditions such as cholestatic or other forms of chronicpruritus as well as acute and chronic organ transplant rejection.

Objects of the present invention are the compounds of formula (I) andtheir aforementioned salts and esters and their use as therapeuticallyactive substances, a process for the manufacture of the said compounds,intermediates, pharmaceutical compositions, medicaments containing thesaid compounds, their pharmaceutically acceptable salts or esters, theuse of the said compounds, salts or esters for the treatment orprophylaxis of disorders or conditions that are associated with theactivity of ATX and/or the biological activity of lysophosphatidic acid(LPA), particularly in the treatment or prophylaxis of renal conditions,liver conditions, inflammatory conditions, conditions of the nervoussystem, conditions of the respiratory system, vascular andcardiovascular conditions, fibrotic diseases, cancer, ocular conditions,metabolic conditions, cholestatic and other forms of chronic pruritusand acute and—chronic organ transplant rejection, and the use of thesaid compounds, salts or esters for the production of medicaments forthe treatment or prophylaxis of renal conditions, liver conditions,inflammatory conditions, conditions of the nervous system, conditions ofthe respiratory system, vascular and cardiovascular conditions, fibroticdiseases, cancer, ocular conditions, metabolic conditions, cholestaticand other forms of chronic pruritus and acute and chronic organtransplant rejection.

The term “alkenyl” denotes a monovalent linear or branched hydrocarbongroup of 2 to 7 carbon atoms with at least one double bond. Inparticular embodiments, alkenyl has 2 to 4 carbon atoms with at leastone double bond. Examples of alkenyl include ethenyl, propenyl,prop-2-enyl, isopropenyl, n-butenyl and iso-butenyl. Particular alkenylgroup is ethenyl.

The term “alkoxy” denotes a group of the formula —O—R′, wherein R′ is analkyl group. Examples of alkoxy group include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Particularalkoxy group include isopropoxy.

The term “alkoxyalkoxy” denotes an alkoxy group wherein at least one ofthe hydrogen atoms of the alkoxy group has been replaced by anotheralkoxy group. Examples of alkoxyalkoxy group include methoxymethoxy,ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy andethoxypropoxy. Particular alkoxyalkoxy groups include methoxymethoxy andmethoxyethoxy.

The term “alkoxyalkoxyalkyl” denotes an alkyl group wherein at least oneof the hydrogen atoms of the alkyl group has been replaced by analkoxyalkoxy group. Examples of alkoxyalkoxyalkyl group includemethoxymethoxymethyl, ethoxymethoxymethyl, methoxyethoxymethyl,ethoxyethoxymethyl, methoxypropoxymethyl, ethoxypropoxymethyl,methoxymethoxyethyl, ethoxymethoxyethyl, methoxyethoxyethyl,ethoxyethoxyethyl, methoxypropoxyethyl and ethoxypropoxyethyl.

The term “alkoxyalkyl” denotes an alkyl group wherein at least one ofthe hydrogen atoms of the alkyl group has been replaced by an alkoxygroup. Exemplary alkoxyalkyl groups include methoxymethyl, ethoxymethyl,methoxyethyl, ethoxyethyl, methoxypropyl, ethoxypropyl andisopropoxymethyl. Particular alkoxyalkyl group include includemethoxymethyl, methoxyethyl and isopropoxymethyl.

The term “alkoxycarbonyl” denotes a group of the formula —C(O)—R′,wherein R′ is an alkoxy group. Examples of alkoxycarbonyl groups includegroups of the formula —C(O)—R′, wherein R′ is methoxy or ethoxy.Particular alkoxycarbonyl group include groups of the formula —C(O)—R′,wherein R′ is methoxy.

The term “alkoxyhaloalkyl” denotes a haloalkyl group wherein at leastone of the hydrogen atoms of the haloalkyl group has been replaced by analkoxy group. Exemplary alkoxyalkyl groups includemethoxytrifluoroethyl, ethoxytrifluoroethyl, methoxytrifluoropropyl andethoxytrifluoropropyl.

The term “alkyl” denotes a monovalent linear or branched saturatedhydrocarbon group of 1 to 12 carbon atoms. In particular embodiments,alkyl has 1 to 7 carbon atoms, and in more particular embodiments 1 to 4carbon atoms. Examples of alkyl include methyl, ethyl, propyl,isopropyl, n-butyl, iso-butyl and sec-butyl, pentyl. Particular alkylgroups include methyl, ethyl, propyl and isopropyl. More particularalkyl group is methyl.

The term “alkylcarbonyl” denotes a group of the formula —C(O)—R′,wherein R′ is an alkyl group. Examples of alkylcarbonyl groups includegroups of the formula —C(O)—R′, wherein R′ is methyl or ethyl.Particular alkylcarbonyl groups include groups of the formula —C(O)—R′,wherein R′ is methyl.

The term “alkylcarbonylamino” denotes a group of the formula—NH—C(O)—R′, wherein R′ is an alkyl group. Examples ofalkylcarbonylamino groups include groups of the formula —NH—C(O)—R′,wherein R′ is methyl or ethyl. Particular a alkylcarbonylamino groupsinclude groups of the formula —NH—C(O)—R′, wherein R′ is methyl.

The term “alkylsulfanyl” denotes a group of the formula —S—R′, whereinR′ is an alkyl group. Examples of alkylsulfanyl groups include groups ofthe formula —S—R′, wherein R′ is methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl or tert-butyl. Particular alkylsulfanyl groups includegroup of the formula —S—R′, wherein R′ is methyl.

The term “alkylsulfinyl” denotes a group of the formula —S(O)—R′,wherein R′ is an alkyl group. Examples of alkylsulfinyl groups includegroups of the formula —S(O)—R′, wherein R′ is methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl or tert-butyl. Particular alkylsulfinylgroups include group of the formula —S(O)—R′, wherein R′ is methyl.

The term “alkylsulfonyl” denotes a group of the formula —S(O)₂—R′,wherein R′ is an alkyl group. Examples of alkylsulfonyl groups includegroups of the formula —S(O)₂—R′, wherein R′ is methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl or tert-butyl. Particular alkylsulfonylgroups include group of the formula —S(O)₂—R′, wherein R′ is methyl.

The term “alkylsulfonylamino” denotes a group of the formula—NH—S(O)₂—R′, wherein R′ is an alkyl group. Examples ofalkylsulfonylamino groups include groups of the formula —NH—S(O)₂—R′,wherein R′ is methyl or ethyl. Particular a alkylsulfonylamino groupsinclude groups of the formula —NH—S(O)₂—R′, wherein R′ is methyl.

The term “amino” denotes a —NH₂ group.

The term “aminoalkyl” denotes an alkyl group wherein at least one of thehydrogen atoms of the alkyl group has been replaced by an aminogroup.Examples of aminoalkyl include aminomethyl, aminoethyl,amino-1-methyl-ethyl, aminopropyl, aminomethylpropyl and aminopropyl.Particular examples are aminomethyl and haminoethyl.

The term “aminosulfonyl” denotes a —S(O)₂—NH₂ group.

The term “carbonyl” denotes a —C(O)— group.

The term “carboxy” denotes a —COOH group.

The term “cyano” denotes a —C≡N group.

The term “cycloalkoxy” denotes a group of the formula —O—R′, wherein R′is a cycloalkyl group. Examples of cycloalkoxy group includecyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxyand cyclooctyloxy. Particular cycloalkoxy group is cyclopropoxy.

The term “cycloalkoxyalkyl” denotes an alkyl group wherein at least oneof the hydrogen atoms of the alkyl group has been replaced by acycloalkoxy group. Examples of cycloalkoxyalkyl groups includecyclopropoxymethyl, cyclopropoxyethyl, cyclobutoxymethyl,cyclobutoxyethyl, cyclopentyloxymethyl, cyclopentyloxyethyl,cyclohexyloxymethyl, cyclohexyloxyethyl, cycloheptyloxymethyl,cycloheptyloxyethyl, cyclooctyloxymethyl and cyclooctyloxyethyl.

The term “cycloalkyl” denotes a monovalent saturated monocyclic orbicyclic hydrocarbon group of 3 to 10 ring carbon atoms. In particularembodiments, cycloalkyl denotes a monovalent saturated monocyclichydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means a ringsystem consisting of two saturated carbocycles having two carbon atomsin common. Examples for monocyclic cycloalkyl are cyclopropyl,cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples forbicyclic cycloalkyl are bicyclo[2.2.1]heptanyl or bicyclo[2.2.2]octanyl.Particular monocyclic cycloalkyl groups are cyclopropyl, cyclobutanyl,cyclopentyl and cyclohexyl. More particular monocyclic cycloalkyl groupis cyclopropyl.

The term “cycloalkylalkoxy” denotes an alkoxy group wherein at least oneof the hydrogen atoms of the alkoxy group is replaced by a cycloalkylgroup. Examples of cycloalkylalkoxy include cyclopropylmethoxy,cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy,cycloheptylmethoxy and cyclooctylmethoxy.

The term “cycloalkylalkoxyalkyl” denotes an alkyl group wherein at leastone of the hydrogen atoms of the alkyl group is replaced by acycloalkylalkoxy group. Examples of cycloalkylalkoxyalkyl includecyclopropylmethoxymethyl, cyclopropylmethoxyethyl,cyclobutylmethoxymethyl, cyclobutylmethoxyethyl,cyclopentylmethoxyethyl, cyclopentylmethoxyethyl,cyclohexylmethoxymethyl, cyclohexylmethoxyethyl,cycloheptylmethoxymethyl, cycloheptylmethoxyethyl,cyclooctylmethoxymethyl and cyclooctylmethoxyethyl.

The term “cycloalkylalkyl” denotes an alkyl group wherein at least oneof the hydrogen atoms of the alkyl group is replaced by a cycloalkylgroup. Examples of cycloalkylalkyl include cyclopropylmethyl,cyclopropylethyl, cyclopropylbutyl, cyclobutylpropyl,2-cyclopropylbutyl, cyclopentylbutyl, cyclohexylmethyl, cyclohexylethyl,bicyclo[4.1.0]heptanylmethyl, bicyclo[4.1.0]heptanylethyl,bicyclo[2.2.2]octanylmethyl, bicyclo[2.2.2]octanylethyl,adamentanylmethyl and adamantanylethyl. Particular examples ofcycloalkylalkyl are cyclohexylmethyl, cyclohexylethyl,bicyclo[4.1.0]heptanylmethyl, bicyclo[4.1.0]heptanylethyl,bicyclo[2.2.2]octanylmethyl, bicyclo[2.2.2]octanylethyl,adamentanylmethyl and adamantanylethyl. Further particular examplescycloalkylalkyl are cyclohexylmethyl, cyclohexylethyl,bicyclo[4.1.0]heptanylmethyl, bicyclo[2.2.2]octanylmethyl,adamentanylmethyl and adamantanylethyl.

The term “cycloalkylcarbonyl” of the formula —C(O)—R′, wherein R′ is acycloalkyl group. Examples of cycloalkylcarbonyl groups include groupsof the formula —C(O)—R′, wherein R′ is cyclopropyl.

The term “cycloalkylsulfanyl” denotes a group of the formula —S—R′,wherein R′ is a cycloalkyl group. Examples of cycloalkylsulfanyl groupsinclude groups of the formula —S—R′, wherein R′ is cyclopropyl.

The term “cycloalkylsulfinyl” denotes a group of the formula —S(O)—R′,wherein R′ is a cycloalkyl group. Examples of cycloalkylsulfinyl groupsinclude groups of the formula —S(O)—R′, wherein R′ is cyclopropyl.

The term “cycloalkylsulfonyl” denotes a group of the formula —S(O)₂—R′,wherein R′ is a cycloalkyl group. Examples of cycloalkylsulfonyl groupsinclude groups of the formula —S(O)₂—R′, wherein R′ is cyclopropyl.

The term “haloalkoxy” denotes an alkoxy group wherein at least one ofthe hydrogen atoms of the alkoxy group has been replaced by the same ordifferent halogen atoms. The term “perhaloalkoxy” denotes an alkoxygroup where all hydrogen atoms of the alkoxy group have been replaced bythe same or different halogen atoms. Examples of haloalkoxy includefluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy,trifluoromethylethoxy, trifluorodimethylethoxy and pentafluoroethoxy.Particular haloalkoxy group is trifluoromethoxy.

The term “haloalkyl” denotes an alkyl group wherein at least one of thehydrogen atoms of the alkyl group has been replaced by the same ordifferent halogen atoms. The term “perhaloalkyl” denotes an alkyl groupwhere all hydrogen atoms of the alkyl group have been replaced by thesame or different halogen atoms. Examples of haloalkyl includefluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl,trifluoromethylethyl and pentafluoroethyl. Particular haloalkyl group istrifluoromethyl.

The term “haloalkylsulfanyl” denotes a group of the formula —S—R′,wherein R′ is a haloalkyl group. Examples of haloalkylsulfanyl groupsinclude groups of the formula —S—R′, wherein R′ is trifluoromethyl.

The term “haloalkylsulfinyl” denotes a group of the formula —S(O)—R′,wherein R′ is a haloalkyl group. Examples of haloalkylsulfinyl groupsinclude groups of the formula —S(O)—R′, wherein R′ is trifluoromethyl.

The term “haloalkylsulfonyl” denotes a group of the formula —S(O)₂—R′,wherein R′ is a haloalkyl group. Examples of haloalkylsulfonyl groupsinclude groups of the formula —S(O)₂—R′, wherein R′ is trifluoromethyl.

The term “halogen” and “halo” are used interchangeably herein and denotefluoro, chloro, bromo, or iodo. Particular halogens are chloro andfluoro.

The term “hydroxy” denotes a —OH group.

The term “hydroxyalkyl” denotes an alkyl group wherein at least one ofthe hydrogen atoms of the alkyl group has been replaced by a hydroxygroup. Examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl,hydroxy-1-methyl-ethyl, hydroxypropyl, hydroxymethylpropyl anddihydroxypropyl. Particular examples are hydroxymethyl and hydroxyethyl.

The term “hydroxyhaloalkyl” denotes a haloalkyl group wherein at leastone of the hydrogen atoms of the haloalkyl group has been replaced by anhydroxy group. Exemplary hydroxyhaloalkyl groups includehydroxytrifluoroethyl and hydroxytrifluoropropyl. Particularhydroxyhaloalkyl groups include hydroxytrifluoroethyl.

The term “naphthylalkenyl” denotes an alkenyl group wherein at least oneof the hydrogen atoms of the alkenyl group has been replaced anaphthynaphthyl. Particular naphthylalkenyl group is naphytylethenyl.

The term “naphthylalkyl” denotes an alkyl group wherein at least one ofthe hydrogen atoms of the alkyl group has been replaced a naphthyl.Particular naphthylalkyl groups are naphthylmethyl, naphthylethyl andnaphthylpropyl.

The term “naphthyloxyalkyl” denotes an alkyl group wherein at least oneof the hydrogen atoms of the alkyl group has been replaced by anaphthyloxy group. Exemplary naphthyloxyalkyl groups includenaphthyloxymethyl, naphthyloxyethyl and naphthyloxypropyl.

The term “phenoxy” denotes a group of the formula —O—R′, wherein R′ is aphenyl.

The term “phenoxyalkyl” denotes an alkyl group wherein at least one ofthe hydrogen atoms of the alkyl group has been replaced by a phenoxygroup. Exemplary phenoxyalkyl groups include phenoxymethyl, phenoxyethyland phenoxypropyl. Particular alkoxyalkyl group is phenoxymethyl.

The term “phenylalkenyl” denotes an alkenyl group wherein at least oneof the hydrogen atoms of the alkenyl group has been replaced a phenyl.Particular phenylalkenyl group is phenylethenyl.

The term “phenylalkyl” denotes an alkyl group wherein at least one ofthe hydrogen atoms of the alkyl group has been replaced a phenyl.Particular phenylalkyl groups are benzyl, phenethyl and phenylpropyl.More particular phenylalkyl groups are benzyl and phenethyl. Furtherparticular phenylalkyl group is benzyl.

The term “phenylalkynyl” denotes an alkynyl group wherein at least oneof the hydrogen atoms of the alkynyl group has been replaced a phenyl.Particular phenylalkynyl group is phenylethynyl.

The term “phenylcyloalkyl” denotes a cycloalkyl group wherein at leastone of the hydrogen atoms of the cycloalkyl group has been replaced aphenyl. Particular phenylcycloalkyl group is phenylcyclopropyl.

The term “pyridinylalkenyl” denotes an alkenyl group wherein at leastone of the hydrogen atoms of the alkenyl group has been replaced apyridinyl. Particular pyridinylalkenyl group is pyridinylethenyl.

The term “pyridinylalkyl” denotes an alkyl group wherein at least one ofthe hydrogen atoms of the alkyl group has been replaced a pyridinyl.Particular pyridinylalkyl groups are pyridinylmethyl, pyridinylethyl andpyridinylpropyl. More particular pyridinylalkyl group is pyridinylethyl.

The term “pyridinylalkynyl” denotes an alkynyl group wherein at leastone of the hydrogen atoms of the alkynyl group has been replaced apyridinyl. Particular pyridinylalkynyl group is pyridinylethynyl.

The term “thiophenylalkenyl” denotes an alkenyl group wherein at leastone of the hydrogen atoms of the alkenyl group has been replaced athiophenyl. Particular thiophenylalkenyl group is thiophenylethenyl.

The term “thiophenylalkyl” denotes an alkyl group wherein at least oneof the hydrogen atoms of the alkyl group has been replaced a thiophenyl.Particular thiophenylalkyl groups are thiophenylmethyl, thiophenylethyland thiophenylpropyl. More particular thiophenylalkyl group isthiophenylmethyl.

The term “thiophenylalkynyl” denotes an alkynyl group wherein at leastone of the hydrogen atoms of the alkynyl group has been replaced athiophenyl. Particular thiophenylalkynyl group is thiophenylethynyl.

The term “pharmaceutically acceptable salts” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, which are not biologically or otherwise undesirable. Thesalts are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike, in particular hydrochloric acid, and organic acids such as aceticacid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleicacid, malonic acid, succinic acid, fumaric acid, tartaric acid, citricacid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid,N-acetylcystein and the like. In addition, these salts may be preparedby addition of an inorganic base or an organic base to the free acid.Salts derived from an inorganic base include, but are not limited to,the sodium, potassium, lithium, ammonium, calcium, magnesium salts andthe like. Salts derived from organic bases include, but are not limitedto salts of primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, such as isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine, lysine,arginine, N-ethylpiperidine, piperidine, polyimine resins and the like.Particular pharmaceutically acceptable salts of compounds of formula (I)are the sodium and potassium salts.

“Pharmaceutically acceptable esters” means that compounds of generalformula (I) may be derivatised at functional groups to providederivatives which are capable of conversion back to the parent compoundsin vivo. Examples of such compounds include physiologically acceptableand metabolically labile ester derivatives, such as methoxymethylesters, methylthiomethyl esters and pivaloyloxymethyl esters.Additionally, any physiologically acceptable equivalents of thecompounds of general formula (I), similar to the metabolically labileesters, which are capable of producing the parent compounds of generalformula (I) in vivo, are within the scope of this invention.

The term “protecting group” (PG) denotes a group which selectivelyblocks a reactive site in a multifunctional compound such that achemical reaction can be carried out selectively at another unprotectedreactive site in the meaning conventionally associated with it insynthetic chemistry. Protecting groups can be removed at the appropriatepoint. Exemplary protecting groups are amino-protecting groups,carboxy-protecting groups or hydroxy-protecting groups. Particularprotecting groups are the tert-butoxycarbonyl (Boc), benzyloxycarbonyl(Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn) groups. Furtherparticular protecting groups are the tert-butoxycarbonyl (Boc) and thefluorenylmethoxycarbonyl (Fmoc) groups. More particular protecting groupis the tert-butoxycarbonyl (Boc) group.

The abbreviation uM means microMolar and is equivalent to the symbol μM.

The abbreviation uL means microliter and is equivalent to the symbol μL.

The abbreviation ug means microgram and is equivalent to the symbol μg.

The compounds of formula (I) can contain several asymmetric centers andcan be present in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, optically purediastereoisomers, mixtures of diastereoisomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates.

According to the Cahn-Ingold-Prelog Convention the asymmetric carbonatom can be of the “R” or “S” configuration.

Also an embodiment of the present invention are compounds according toformula (I) as described herein and pharmaceutically acceptable salts oresters thereof, in particular compounds according to formula (I) asdescribed herein and pharmaceutically acceptable salts thereof, moreparticularly compounds according to formula (I) as described herein.

A further embodiment of the present invention are compounds according toformula (I) as described herein, wherein R¹ is substituted phenyl,substituted phenylalkyl, substituted phenylalkenyl, substitutednaphthyl, substituted indolyl, substituted quinolyl, or substitutedisoquinolyl, wherein substituted phenyl, substituted phenylalkyl,substituted phenylalkenyl, substituted naphthyl, substituted indolyl,substituted quinolyl and substituted isoquinolyl are substituted withR⁷, R⁸ and R⁹.

A particular embodiment of the present invention are compounds accordingto formula (I) as described herein, wherein R¹ is phenylalkylsubstituted with R⁷, R⁸ and R⁹.

In a further embodiment of the present invention are compounds accordingto formula (I) as described herein, wherein R¹ is 3,5-dichlorobenzyl,4-trifluoromethoxybenzyl or 4-trifluoromethoxyphenylethyl.

The present invention also relates to compounds according to formula (I)as described herein, wherein R¹ is substituted phenyl or substitutedpyridinyl, wherein substituted phenyl and substituted pyridinyl aresubstituted with R¹⁰, R¹¹ and R¹².

A further particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R² is phenylsubstituted phenyl with R¹⁰, R¹¹ and R¹².

Another further embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R² is4-aminosulfonylphenyl, 3-fluoro-4-aminosulfonylphenyl,3-aminosulfonylpyridin-6-yl or 2-aminosulfonylpyridin-5-yl.

Another embodiment of the present invention are compounds according toformula (I) as described herein, wherein Y is —OC(O)— or —C(O)—.

A more particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein A is —N—.

Also an embodiment of the present invention are compounds according toformula (I) as described herein, wherein W is —C(O)— or —S(O)₂—.

Another embodiment of the present invention are compounds according toformula (I) as described herein, wherein W is —C(O)—.

Another embodiment of the present invention are compounds according toformula (I) as described herein, wherein R⁷, R⁸ and R⁹ are independentlyselected from H, alkoxy, haloalkoxy, halogen, alkylsulfonyl and phenylsubstituted with one halogen, and wherein at least one of R⁷, R⁸ and R⁹is not H.

A further particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R⁷ is alkoxy,haloalkoxy, halogen or phenyl substituted with one halogen.

A further particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R⁷ is haloalkoxyor halogen.

A further particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R⁸ is H, halogenor alkylsulfonyl.

A further particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R⁸ is H orhalogen.

A further particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R⁹ is H.

A further particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R¹⁰ isaminosulfonyl.

A further particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R¹¹ and R¹² areindependently selected from H, alkyl and halogen.

A further particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R¹¹ and R¹² areindependently selected from H and halogen.

A further particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein m and n are 1.

A further particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein m, n, p and q are1.

A further particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R² is4-aminosulfonylphenyl and of formula (Ia).

Particular examples of compounds of formula (I) as described herein areselected from

-   (3aR,6aS)-3,5-dichlorobenzyl    5-(4-(N-methylsulfamoyl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(5-hydroxypicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(4-hydroxybenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   trans-3,5-dichlorobenzyl    2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(5-sulfamoylthiophene-2-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(4-aminobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(5-aminopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(4-cyanobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(4-(methoxycarbonyl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   4-{(3    aS,8aR)-6-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-octahydro-pyrrolo[3,4-d]azepine-2-carbonyl}-benzenesulfonamide;-   (3aS,6aS)-5-(3-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   (3aS,6aS)-5-(6-oxo-1,6-dihydro-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   (3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   (3aS,6aS)-5-(1-methyl-4-sulfamoyl-1H-pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   (3aS,6aS)-5-(1-methyl-5-sulfamoyl-1H-pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   (3aS,6aS)-5-(6-sulfamoyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   (3aS,6aS)-5-(5-hydroxy-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy benzyl ester;-   (3aS,6aS)-5-(4-hydroxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(4-acetamidobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(5-acetamidopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(4-sulfamoylphenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(4-(1H-tetrazol-5-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   4-((3aR,6aS)-5-((3,5-dichlorobenzyloxy)carbonyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzoic    acid;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(5-(methylsulfonamido)picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   (3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 3-chloro-5-methanesulfonyl-benzyl ester;-   (3aR,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 2-fluoro-4-trifluoromethoxy-benzyl ester;-   (3aR,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   (3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   4-{(3aR,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;-   4-{(3aR,6aR)-5-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;-   4-[(3    aR,6aS)-5-(4-isopropoxy-naphthalene-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;-   4-{(3    aR,6aS)-5-[1-(2,2,2-trifluoro-ethoxy)-isoquinoline-3-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;-   4-[(3    aR,6aS)-5-(1-Methyl-5-trifluoromethoxy-1H-indole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;-   4-[(3    aR,6aS)-5-(4-Isopropoxy-quinoline-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;-   4-[(3    aS,6aR)-5-(4′-chloro-biphenyl-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;-   4-{(3aS,6aR)-5-[3-(2-fluoro-4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;-   4-{(3aS,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;-   4-((3    aR,6aR)-5-(3-(2-fluoro-4-(trifluoromethoxy)phenyl)propanoyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide;-   (+)-trans-3,5-dichlorobenzyl    2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate;-   (−)-trans-3,5-dichlorobenzyl    2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate;    -   and pharmaceutically acceptable salts thereof.

Also particular examples of compounds of formula (I) as described hereinare selected from

-   (3aR,6aS)-3,5-dichlorobenzyl    5-(4-(N-methylsulfamoyl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(5-hydroxypicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(4-hydroxybenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   trans-3,5-dichlorobenzyl    2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(5-sulfamoylthiophene-2-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(4-aminobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(5-aminopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(4-cyanobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(4-(methoxycarbonyl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   4-{(3    aS,8aR)-6-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-octahydro-pyrrolo[3,4-d]azepine-2-carbonyl}-benzenesulfonamide;-   (3aS,6aS)-5-(3-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   (3aS,6aS)-5-(6-oxo-1,6-dihydro-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   (3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   (3aS,6aS)-5-(1-methyl-4-sulfamoyl-1H-pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   (3aS,6aS)-5-(1-methyl-5-sulfamoyl-1H-pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   (3aS,6aS)-5-(6-sulfamoyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   (3aS,6aS)-5-(5-hydroxy-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy benzyl ester;-   (3aS,6aS)-5-(4-hydroxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(4-acetamidobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(5-acetamidopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(4-sulfamoylphenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(4-(1H-tetrazol-5-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   4-((3aR,6aS)-5-((3,5-dichlorobenzyloxy)carbonyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzoic    acid;-   (3aR,6aS)-3,5-dichlorobenzyl    5-(5-(methylsulfonamido)picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   (3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 3-chloro-5-methanesulfonyl-benzyl ester;-   (3aR,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 2-fluoro-4-trifluoromethoxy-benzyl ester;-   (3aR,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   (3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   4-{(3aR,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;-   4-{(3aR,6aR)-5-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;-   4-[(3aR,6aS)-5-(4-isopropoxy-naphthalene-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;-   4-{(3    aR,6aS)-5-[1-(2,2,2-trifluoro-ethoxy)-isoquinoline-3-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;-   4-[(3aR,6aS)-5-(1-Methyl-5-trifluoromethoxy-1H-indole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;-   4-[(3aR,6aS)-5-(4-Isopropoxy-quinoline-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;-   4-[(3aS,6aR)-5-(4′-chloro-biphenyl-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;-   4-{(3    aS,6aR)-5-[3-(2-fluoro-4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;-   4-{(3    aS,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;-   4-((3aR,6aR)-5-(3-(2-fluoro-4-(trifluoromethoxy)phenyl)propanoyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide;-   (+)-trans-3,5-dichlorobenzyl    2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate;-   (−)-trans-3,5-dichlorobenzyl    2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate;-   (3aS,6aS)-5-(2-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   5-{(3aR,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-pyridine-2-sulfonic    acid amide;-   5-((3aS,6aS)-5-(4-ethoxyquinoline-2-carbonyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)pyridine-2-sulfonamide;-   (3aS,6aS)-5-(3-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester;-   (3aS,6aS)-5-(6-sulfamoyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester;-   (3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzylester;-   (3aS,6aS)-5-(2-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester;-   (3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester; and    pharmaceutically acceptable salts thereof.

Further particular examples of compounds of formula (I) as describedherein are selected from

-   (3aR,6aS)-3,5-dichlorobenzyl    5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   (3aS,6aS)-5-(3-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   (3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   (3aS,6aS)-5-(6-sulfamoyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   (3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   4-{(3    aR,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;    -   and pharmaceutically acceptable salts thereof.

Also further particular examples of compounds of formula (I) asdescribed herein are selected from

-   (3aR,6aS)-3,5-dichlorobenzyl    5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;-   (3aS,6aS)-5-(3-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   (3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   (3aS,6aS)-5-(6-sulfamoyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   (3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-trifluoromethoxy-benzyl ester;-   4-{(3aR,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;-   (3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic    acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester;    -   and pharmaceutically acceptable salts thereof. Processes for the        manufacture of compounds of formula (I) as described herein are        an object of the invention.

The preparation of compounds of formula (I) of the present invention maybe carried out in sequential or convergent synthetic routes. Synthesesof the invention are shown in the following general schemes. The skillsrequired for carrying out the reactions and purifications of theresulting products are known to those persons skilled in the art. Incase a mixture of enantiomers or diastereoisomers is produced during areaction, these enantiomers or diastereoisomers can be separated bymethods described herein or known to the man skilled in the art such ase.g. (chiral) chromatography or crystallization. The substituents andindices used in the following description of the processes have thesignificance given herein.

Compounds of general formula (I) can be synthesised from amine precursor1 and appropriate reagents, using methods well known in the art.

For instance, amine 1 is reacted with a suitable chloroformate ester offormula R¹—O—C(O)—Cl (2), or with an imidazole-1-carboxylate ester offormula (3), leading to a compound of formula (I) wherein Y is —OC(O)—.

The reaction is performed in a suitable solvent such as dichloromethane,tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water, ormixtures thereof, in the presence of a base, e.g., triethylamine,diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassiumcarbonate, at temperatures between 0° C. and the boiling point of thesolvent or solvent mixture.

Chloroformate esters 2 are commercially available or can be synthesisedfrom the corresponding alcohol of formula R¹—OH, by reaction withphosgene or a phosgene equivalent (e.g., diphosgene, triphosgene), asdescribed in the literature.

Imidazole-1-carboxylate esters 3 are synthesised from the correspondingalcohols of formula R¹—OH, by reaction with 1,1′-carbonyldiimidazole.The reaction is performed at room temperature, in a solvent such asdichloromethane, tetrahydrofuran or acetonitrile. Theimidazole-1-carboxylate esters 3 are typically not isolated but directlyreacted with amines 1 as described above.

Alcohols of formula R¹—OH are commercially available or can be producedby methods described herein or known in the art.

Alternatively, amine 1 is reacted with a suitableN-(chlorocarbonyl)amine of formula R¹—N(R⁵)—C(O)—Cl (4), or, in the casewhere R⁵ is H, with an isocyanate of formula R¹—NCO (5), leading tocompounds of formula (I) wherein Y is —NR⁵C(O)—.

N-(Chlorocarbonyl)amines (4) are synthesised from the correspondingamines of formula R¹—N(R⁵)H by reaction with phosgene or a phosgeneequivalent, as described in the literature.

Isocyanates 5 are commercially available or can be prepared from thecorresponding amines of formula R¹—NH₂, by reaction with phosgene or aphosgene equivalent (e.g., diphosgene, triphosgene,1,1′-carbonyldiimidazole) using conditions described in the literature.

Alternatively, amine 1 is reacted with a suitable carboxylic acid offormula R¹—COOH (6) leading to a compound of formula (I), wherein Y is—C(O)—. The reaction is performed in the presence of a coupling agentsuch as 1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate or bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate, in aprotic solvents such as dichloromethane,tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone andmixtures thereof at temperatures between −40° C. and 80° C. in thepresence or absence of a base such as triethylamine,diisopropylethylamine, 4-methylmorpholine and/or4-(dimethylamino)pyridine.

Amine 1 can also be reacted with suitable acylating reagents such asacyl chlorides of formula R¹—COCl (7) to lead to compounds of formula(I) wherein Y is —C(O)—. The reaction is performed in a solvent such asdichloromethane, tetrahydrofuran, or N,N-dimethylformamide, in thepresence of a base such as triethylamine or 4-methylmorpholine, attemperatures between 0° C. and 80° C.

Carboxylic acids (6) and acyl halides (7) are commercially available orcan be prepared as described herein or in the literature.

Alternatively, amine 1 is reacted with a suitable sulfonyl chloride offormula R¹—SO₂Cl (8), leading to compounds of formula (I) wherein Y is—S(O₂)—. The reaction is performed in a suitable solvent such asdichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile,acetone, water, or mixtures thereof, in the presence of a base, e.g.,triethylamine, diisopropylethylamine, pyridine, potassiumhydrogencarbonate, potassium carbonate, at temperatures between 0° C.and the boiling point of the solvent or solvent mixture.

Sulfonyl chlorides (8) are commercially available or can be synthesisedas described herein or in the literature.

Alternatively, amine 1 is reacted with a suitable chloro-oxadiazolereagent of general formula 9, or with oxadiazolone reagent 10, leadingto a compound of formula (I), wherein Y is

In the case where compounds of formula (I) are produced from amine 1 andchloro-oxadiazole 9, the reaction is performed in the presence of abase, e.g., potassium carbonate, triethylamine, or1,8-diazabicyclo[5.4.0]undec-7-ene, in a solvent such as toluene,ethanol, N,N-dimethylformamide, or 1,4-dioxane at temperatures between20° C. and 150° C.

In the case where compounds of formula (I) are produced from amine 1 andoxadiazolone 10, the reaction is performed in the presence of a couplingagent, e.g. benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate and a base, e.g., diisopropylethylamine or4-methylmorpholine, in a solvent such as N,N-dimethylformamide, attemperatures between 20° C. and 100° C. as described in the literature.

Oxadiazolones 10 are commercially available or can be produced asdescribed in the literature.

Chloro-oxadiazoles 9 are commercially available or can be produced fromthe corresponding oxadiazolones, by reaction with a suitablehalogenating reagent, e.g. phosphorus oxychloride and/or phosphoruspentachloride, at temperatures between 60° C. and 120° C.

Alternatively, amine 1 is reacted with a suitable halo-thiadiazolereagent of general formula 11 (X═Cl or Br), or with thiadiazolethionereagent 12, leading to compounds of (I) wherein Y is

In the case where compounds of formula (I) are produced from amine 1 andhalo-thiadiazole 11, the reaction is performed in the presence of abase, e.g. potassium carbonate, triethylamine or1,8-diazabicyclo[5.4.0]undec-7-ene, in a solvent such as toluene,ethanol, N,N-dimethylformamide or 1,4-dioxane, at temperatures between20° C. and 150° C.

In the case where compounds of formula (I) are produced from amine 1 andthiadiazolethione 12, the reaction is performed in a solvent such asethanol or N,N-dimethylformamide at temperatures between 20° C. and 100°C. as described in the literature.

Thiadiazolethiones 12 are commercially available or can be produced asdescribed in the literature.

Halo-thiadiazoles 11 are commercially available or can be produced asdescribed in the literature.

Amines of general formula 1 are synthesised from suitably protectedprecursors 13.

Suitable protective groups (PG) are tert-butoxycarbonyl,benzyloxycarbonyl and substituted benzyloxycarbonyl such as 3,5-dichlorobenzyloxycarbonyl. The deprotection of intermediates 13 can be performedusing methods and reagents known in the art.

For instance, in the case where PG is optionally substitutedbenzyloxycarbonyl, the deprotection may be performed by hydrogenation atpressures between 1 bar and 100 bar, in the presence of a suitablecatalyst such as palladium on activated charcoal, at temperaturesbetween 20° C. and 150° C. in solvents such as methanol or ethanol.

Alternatively, in the case where PG is tert-butoxycarbonyl, thedeprotection may be performed in the presence of a suitable acid, e.g.,hydrochloric acid or trifluoroacetic acid, in a solvent such as water,2-propanol, dichloromethane, or 1,4-dioxane at temperatures between 0°C. and 30° C.

Intermediates 13, wherein A is N are represented by general structure13A.

PG is a suitable protective group, e.g., tert-butoxycarbonyl,benzyloxycarbonyl and substituted benzyloxycarbonyl such as 3,5-dichlorobenzyloxycarbonyl.

Intermediates 13A can be produced from amine precursors of generalformula 14 by reaction with appropriate reagents, using methods known inthe art.

For instance, 14 is reacted with alkylating agents of general formulaX—CR³R⁴—R² (15) where X is a leaving group such as Cl, Br, I, orOSO₂CH₃, leading to 13A, wherein W is —CR³R⁴—. This reaction isperformed in a solvent such as tetrahydrofuran or N,N-dimethylformamide,in the presence of a base, e.g. triethylamine or potassium carbonate, attemperatures between 0° C. and 100° C.

Alternatively, for compounds of formula 13A, wherein W is —CR³R⁴—, R⁴ ishydrogen, alkyl or cycloalkyl, and R³ is H, amine 14 is reacted withaldehydes or ketones of general formula R⁴—C(O)—R² (16) in a reductiveamination reaction, leading to 13A. This reaction is performed in thepresence of a suitable reducing agent, e.g., sodium borohydride orsodium triacetoxyborohydride, in a solvent such as methanol, aceticacid, tetrahydrofuran, 1,2-dichloroethane or mixtures thereof, attemperatures between 0° C. and 50° C.

Alternatively, amine 14 is reacted with a suitable carboxylic acid offormula R²—COOH (17), leading to compounds of formula 13A, wherein W is—C(O)—. The reaction is performed in the presence of a coupling agentsuch as 1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate or bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate, in aprotic solvents such as dichloromethane,tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone andmixtures thereof at temperatures between −40° C. and 80° C. in thepresence or absence of a base such as triethylamine,diisopropylethylamine, 4-methylmorpholine and/or4-(dimethylamino)pyridine.

Alternatively, amine 14 is reacted with a suitable sulfonyl chloride offormula R²—SO₂Cl (18), leading to compounds of formula 13A, wherein W is—S(O₂)—. The reaction is performed in a suitable solvent such asdichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile,acetone, water, or mixtures thereof, in the presence of a base, e.g.triethylamine, diisopropylethylamine, pyridine, potassiumhydrogencarbonate, potassium carbonate, at temperatures between 0° C.and the boiling point of the solvent or solvent mixture.

Amines 14, alkylating agents 15, aldehydes/ketones 16, carboxylic acids17, sulfonyl chlorides 18, and amines 22 are commercially available orcan be synthesised as described in the literature or in the experimentalsection.

Intermediates 13 wherein A is C—H are represented by general formula13B, wherein PG is a suitable protective group, e.g.tert-butoxycarbonyl, benzyloxycarbonyl and substituted benzyloxycarbonylsuch as 3,5-dichloro benzyloxycarbonyl.

Compound 13B, wherein W is —NR⁶—, is produced from ketone 19 by reactionwith an amine of formula HN(R⁶)R² (20) in the presence of a suitablereducing agent, e.g. sodium borohydride or sodium triacetoxyborohydride,in a solvent such as methanol, acetic acid, tetrahydrofuran,1,2-dichloroethane, or mixtures thereof, at temperatures between 0° C.and 50° C.

Ketones 19 and amines 20 are commercially available or can be preparedas described in the literature.

Compound 13B, wherein W is —O— or —S—, is produced from alcohol 21 usingmethods and reagents known in the art.

For instance, alcohol 24 is reacted at room temperature with phenolHO—R² or thiophenol HS—R² in the presence of triphenylphosphine and andialkylazodicarboxylate, e.g. diisopropylazodicarboxylate ordiethylazodicarboxylate, in a solvent such as toluene, dichloromethane,or tetrahydrofuran, leading to 13B, wherein W is —O— or —S—.

Alternatively, conversion of alcohol 21 to the correspondingmethanesulfonate using methanesulfonyl chloride in the presence of abase, e.g. triethylamine, in a solvent such as dichloromethane ortetrahydrofuran, at temperatures between −20° C. and +30° C., andtreatment of the methanesulfonate intermediate with phenol HO—R² orthiophenol HS—R² in the presence of a base, e.g., potassium carbonate,in a solvent such as N,N-dimethylformamide or acetonitrile, attemperatures between 20° C. and 100° C., leads to 13B, wherein W is —O—or —S—.

Compound 13B, wherein W is —SO₂—, is produced from compound 13B, whereinW is —S—, by oxidation with a suitable reagent, e.g., hydrogen peroxideor 3-chloroperbenzoic acid, in a solvent such as formic acid, aceticacid, or dichloromethane, at temperatures between 0° C. and 50° C.

Alcohols 21 are produced from ketones 19 using a suitable reducingagent, e.g., sodium borohydride, in a solvent such as methanol, attemperatures between 0° C. and 50° C.

Compounds of formula (I), wherein A is N can be produced from amineprecursors of general formula 22 by reaction with appropriate reagents,using methods known in the art.

For instance, an amine of formula 22 is reacted with alkylating agentsof general formula X—CR³R⁴—R² (15) where X is a leaving group such asCl, Br, I, or OSO₂CH₃, leading to compounds of formula (I), wherein A isN and W is —CR³R⁴—. This reaction is performed in a solvent such astetrahydrofuran or N,N-dimethylformamide, in the presence of a base,e.g., triethylamine or potassium carbonate, at temperatures between 0°C. and 100° C.

Alternatively, an amine of formula 22 is reacted with aldehydes orketones of general formula R⁴—C(O)—R² (16) in a reductive aminationreaction, leading to compounds of formula (I) wherein A is N, W is—CR³R⁴—, R⁴ is hydrogen, alkyl or cycloalkyl, and R³ is H. This reactionis performed in the presence of a suitable reducing agent, e.g. sodiumborohydride or sodium triacetoxyborohydride, in a solvent such asmethanol, acetic acid, tetrahydrofuran, 1,2-dichloroethane or mixturesthereof, at temperatures between 0° C. and 50° C.

Alternatively, amine 22 is reacted with a suitable carboxylic acid offormula R²—COOH (17), leading to compounds of formula (I) wherein A is Nand W is —C(O)—. The reaction is performed in the presence of a couplingagent such as 1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate or bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate, in aprotic solvents such as dichloromethane,tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone andmixtures thereof at temperatures between −40° C. and 80° C. in thepresence or absence of a base such as triethylamine,diisopropylethylamine, 4-methylmorpholine and/or4-(dimethylamino)pyridine.

Alternatively, amine 22 is reacted with a suitable sulfonyl chloride offormula R²—SO₂Cl (18), leading to (I) wherein A is N and W is —S(O₂)—.The reaction is performed in a suitable solvent such as dichloromethane,tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water, ormixtures thereof, in the presence of a base, e.g. triethylamine,diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassiumcarbonate, at temperatures between 0° C. and the boiling point of thesolvent or solvent mixture.

Amines 22 can be synthesised from their tert-butyl carbamate derivativesof formula 23 by carbamate deprotection. The deprotection may beperformed in the presence of a suitable acid, e.g., hydrochloric acid ortrifluoroacetic acid, in a solvent such as water, 2-propanol,dichloromethane, or 1,4-dioxane, at temperatures between 0° C. and 30°C.

tert-Butyl carbamates 23 can be synthesised from amine precursors offormula 24 and appropriate reagents, using methods well known in theart.

For instance, an amine of formula 24 is reacted with a suitablechloroformate ester of formula R¹—O—C(O)—Cl (2), or with animidazole-1-carboxylate ester of formula (3), leading to compounds offormula 23, wherein Y is —OC(O)—. The reaction is performed in asuitable solvent such as dichloromethane, tetrahydrofuran,N,N-dimethylformamide, acetonitrile, acetone, water, or mixturesthereof, in the presence of a base, e.g. triethylamine,diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassiumcarbonate, at temperatures between 0° C. and the boiling point of thesolvent or solvent mixture.

Alternatively, an amine of formula 24 is reacted with a suitableN-(chlorocarbonyl)amine of formula R¹—N(R⁵)—C(O)—Cl (4) leading tocompounds of formula 23, wherein Y is —NR⁵C(O)—, or with an isocyanateof formula R¹—NCO (5) leading to compounds of formula 23, wherein Y is—NR⁵C(O)— and R⁵ is H.

Alternatively, amine 24 is reacted with a suitable carboxylic acid offormula R¹—COOH (6) leading to compounds of formula 23, wherein Y is—C(O)—. The reaction is performed in the presence of a coupling agentsuch as 1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate or bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate, in aprotic solvents such as dichloromethane,tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone andmixtures thereof at temperatures between −40° C. and 80° C. in thepresence or absence of a base such as triethylamine,diisopropylethylamine, 4-methylmorpholine and/or4-(dimethylamino)pyridine.

Amine 24 can also be reacted with suitable acylating reagents, such asacyl chlorides of formula R¹—COCl (7) to provide compounds of formula23, wherein Y is —C(O)—. The reaction is performed in a solvent such asdichloromethane, tetrahydrofuran, or N,N-dimethylformamide, in thepresence of a base such as triethylamine or 4-methylmorpholine, attemperatures between 0° C. and 80° C.

Alternatively, amine 24 is reacted with a suitable sulfonyl chloride, offormula R¹—SO₂Cl (8), leading to compounds of formula 23, wherein Y is—S(O₂)—. The reaction is performed in a suitable solvent such asdichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile,acetone, water, or mixtures thereof, in the presence of a base, e.g.triethylamine, diisopropylethylamine, pyridine, potassiumhydrogencarbonate, potassium carbonate, at temperatures between 0° C.and the boiling point of the solvent or solvent mixture.

Alternatively, amine 24 is reacted with a suitable chloro-oxadiazolereagent of general formula 9, or with oxadiazolone reagent 10, leadingto compounds of formula 23, wherein Y is

In the case where 23 is produced from amine 24 and chloro-oxadiazole 9,the reaction is performed in the presence of a base, e.g. potassiumcarbonate, triethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene, in asolvent such as toluene, ethanol, N,N-dimethylformamide, or 1,4-dioxane,at temperatures between 20° C. and 150° C.

In the case where 23 is produced from amine 24 and oxadiazolone 10, thereaction is performed in the presence of a coupling agent, e.g.,benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate, and a base, e.g. diisopropylethylamine or4-methylmorpholine, in a solvent such as N,N-dimethylformamide, attemperatures between 20° C. and 100° C., as described in theliterature).

Alternatively, amine 24 is reacted with a suitable halo-thiadiazolereagent of general formula 11 (X is Cl or Br), or with thiadiazolethionereagent 12, leading to compounds of formula 23, wherein Y is

In the case where 23 is produced from amine 24 and halo-thiadiazole 11,the reaction is performed in the presence of a base, e.g. potassiumcarbonate, triethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene, in asolvent such as toluene, ethanol, N,N-dimethylformamide, or 1,4-dioxane,at temperatures between 20° C. and 150° C.

In the case where 23 is produced from amine 24 and thiadiazolethione 12,the reaction is performed in a solvent such as ethanol orN,N-dimethylformamide, at temperatures between 20° C. and 100° C., asdescribed in the literature.

Alternatively, amine 24 is acylated with a haloalkanoyl halide, e.g.,bromoacetyl chloride, in the presence of a base, e.g. triethylamine, ina solvent such as dichloromethane or tetrahydrofuran, at temperaturesbetween −78° C. and +20° C., leading to the corresponding haloalkanamideintermediate, which in the presence of a base, e.g. potassium carbonateor caesium carbonate, in a solvent such as N,N-dimethylformamideundergoes a nucleophilic substitution reaction with a substitutedphenol, leading to compounds of formula 28, wherein Y is —C(O)— and R¹is substituted phenoxyalkyl.

Amines of formula 24 are commercially available or can be produced asdescribed in the literature or in the experimental section.

Also an embodiment of the present invention is a process to prepare acompound of formula (I) as defined above comprising the reaction of acompound of formula (II) in the presence of a compound of formula (III);

-   -   wherein R¹, R², A, W, m, n, p and q are as defined above, Y is        —OC(O)—.

In particular, in the presence of a coupling agent such asO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate, in a solvent such as N,N-dimethylformamide, in thepresence of a base such as 4-methylmorpholine and at a temperaturecomprised between −78° C. and reflux, particularly between −10° C. androom temperature.

Also an object of the present invention is a compound according toformula (I) as described herein for use as a therapeutically activesubstance.

Likewise an object of the present invention is a pharmaceuticalcomposition comprising a compound according to formula (I) as describedherein and a therapeutically inert carrier.

An object of the invention is the use of a compound according to formula(I) as described herein for the treatment or prophylaxis of renalconditions, liver conditions, inflammatory conditions, conditions of thenervous system, conditions of the respiratory system, vascular andcardiovascular conditions, fibrotic diseases, cancer, ocular conditions,metabolic conditions, cholestatic and other forms of chronic pruritusand acute and chronic organ transplant rejection.

Renal conditions include, but are not limited to, acute kidney injuryand chronic renal disease with and without proteinuria includingend-stage renal disease (ESRD). In more detail, this includes decreasedcreatinine clearance and decreased glomerular filtration rate,micro-albuminuria, albuminuria and proteinuria, glomerulosclerosis withexpansion of reticulated mesangial matrix with or without significanthypercellularity (particularly diabetic nephropathy and amyloidosis),focal thrombosis of glomerular capillaries (particularly thromboticmicroangiopathies), global fibrinoid necrosis, ischemic lesions,malignant nephrosclerosis (such as ischemic retraction, reduced renalblood flow and renal arteriopathy), swelling and proliferation ofintracapillary (endothelial and mesangial) and/or extracapillary cells(crescents) like in glomerular nephritis entities, focal segmentalglomerular sclerosis, IgA nephropathy, vasculitides/systemic diseases aswell as acute and chronic kidney transplant rejection.

Liver conditions include, but are not limited to, liver cirrhosis,hepatic congestion, cholestatic liver disease including pruritus,nonalcoholic steatohepatitis and acute and chronic liver transplantrejection.

Inflammatory conditions include, but are not limited to, arthritis,osteoarthritis, multiple sclerosis, systemic lupus erythematodes,inflammatory bowel disease, abnormal evacuation disorder and the like aswell as inflammatory airways diseases such as idiopathic pulmonaryfibrosis (IPF), chronic obstructive pulmonary disease (COPD) or chronicasthma bronchiale.

Further conditions of the respiratory system include, but are notlimited to, other diffuse parenchymal lung diseases of differentetiologies including iatrogenic drug-induced fibrosis, occupationaland/or environmental induced fibrosis, systemic diseases andvasculitides, granulomatous diseases (sarcoidosis, hypersensitivitypneumonia), collagen vascular disease, alveolar proteinosis, Langerhanscell granulomatosis, lymphangioleiomyomatosis, inherited diseases(Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis,metabolic storage disorders, familial interstitial lung disease),radiation induced fibrosis, silicosis, asbestos induced pulmonaryfibrosis or acute respiratory distress syndrome (ARDS).

Conditions of the nervous system include, but are not limited to,neuropathic pain, schizophrenia, neuro-inflammation (e.g. astrogliosis),peripheral and/or autonomic (diabetic) neuropathies and the like.

Vascular conditions include, but are not limited to, atherosclerosis,thrombotic vascular disease as well as thrombotic microangiopathies,proliferative arteriopathy (such as swollen myointimal cells surroundedby mucinous extracellular matrix and nodular thickening),atherosclerosis, decreased vascular compliance (such as stiffness,reduced ventricular compliance and reduced vascular compliance),endothelial dysfunction and the like.

Cardiovascular conditions include, but are not limited to, acutecoronary syndrome, coronary heart disease, myocardial infarction,arterial and pulmonary hypertension, cardiac arrhythmia such as atrialfibrillation, stroke and other vascular damage.

Fibrotic diseases include, but are not limited to myocardial andvascular fibrosis, renal fibrosis, liver fibrosis, pulmonary fibrosis,skin fibrosis, scleroderma and encapsulating peritonitis.

In a particular embodiment, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis of organ or skin fibrosis.

In another embodiment, the fibrotic disease is renal tubulo-interstitialfibrosis or glomerulosclerosis.

In another embodiment, the fibrotic disease is non-alcoholic liversteatosis, liver fibrosis or liver cirrhosis.

In another embodiment, the fibrotic disease is idiopathic pulmonaryfibrosis.

Cancer and cancer metastasis include, but are not limited to, breastcancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma,glioma, hepatic carcinoma, gastrointestinal cancers and progression andmetastatic aggressiveness thereof.

Ocular conditions include, but are not limited to, proliferative andnon-proliferative (diabetic) retinopathy, dry and wet age-relatedmacular degeneration (AMD), macular edema, central arterial/venousocclusion, traumatic injury, glaucoma and the like.

Metabolic conditions include, but are not limited to, obesity anddiabetes.

In another embodiment, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis of cholestatic or non-cholestatic chronicpruritus.

The present invention also relates to the use of a compound according toformula (I) as described herein for the treatment or prophylaxis ofrenal conditions, liver conditions, inflammatory conditions, conditionsof the nervous system, fibrotic diseases and acute and chronic organtransplant rejection.

The present invention also relates to the use of a compound according toformula (I) as described herein for the treatment or prophylaxis ofrenal conditions, liver conditions and fibrotic diseases.

A particular embodiment of the present invention is a compound accordingto formula (I) as described herein for the treatment or prophylaxis ofrenal conditions, liver conditions, inflammatory conditions, conditionsof the nervous system, fibrotic diseases and acute and chronic organtransplant rejection.

A particular embodiment of the present invention is a compound accordingto formula (I) as described herein for the treatment or prophylaxis ofrenal conditions, liver conditions and fibrotic diseases.

The present invention also relates to the use of a compound according toformula (I) as described herein for the preparation of a medicament forthe treatment or prophylaxis of renal conditions, liver conditions,inflammatory conditions, conditions of the nervous system, fibroticdiseases and acute and chronic organ transplant rejection.

The present invention also relates to the use of a compound according toformula (I) as described herein for the preparation of a medicament forthe treatment or prophylaxis of renal conditions, liver conditions andfibrotic diseases.

Also an object of the invention is a method for the treatment orprophylaxis of renal conditions, liver conditions, inflammatoryconditions, conditions of the nervous system, fibrotic diseases andacute and chronic organ transplant rejection, which method comprisesadministering an effective amount of a compound according to formula (I)as described herein.

Also an object of the invention is a method for the treatment orprophylaxis of renal conditions, liver conditions and fibrotic diseases,which method comprises administering an effective amount of a compoundaccording to formula (I) as described herein.

In a particular embodiment, the renal condition is selected from thegroup consisting of acute kidney injury, chronic kidney disease,diabetic nephropathy, acute kidney transplant rejection and chronicallograft nephropathy.

In another particular embodiment, the renal condition is acute kidneyinjury.

In another particular embodiment, the renal condition is chronic kidneydisease.

In a further particular embodiment, the renal condition is diabeticnephropathy.

In another particular embodiment, the renal condition is acute kidneytransplant rejection.

In another particular embodiment, the renal condition is chronicallograft nephropathy.

In a particular embodiment, the liver condition is acute and chronicliver transplant rejection

In a particular embodiment, the inflammatory condition is arthritis.

In a particular embodiment, the condition of the nervous system isneuropathic pain.

In another embodiment, the fibrotic disease is encapsulating peritonitis

In another embodiment, the fibrotic disease is idiopathic pulmonaryfibrosis.

In another embodiment, the fibrotic disease is non-alcoholic liversteatosis, liver fibrosis or liver cirrhosis.

Also an embodiment of the present invention are compounds of formula (I)as described herein, when manufactured according to any one of thedescribed processes.

Assay Procedures Production of Human Full Length ATX, with and withoutHis Tag Autotaxin (ATX-ENPP2) Cloning:

cDNA was prepared from commercial human hematopoietic cells total RNAand used as template in overlapping PCR to generate a full length humanENPP2 ORF with or without a 3′-6×His tag. These full length inserts werecloned into the pcDNA3.1V5-His TOPO (Invitrogen) vector. The DNAsequences of several single clones were verified. The DNA from a correctfull length clone was used to transfect Hek293 cells for verification ofprotein expression. The sequence of the encoded ENPP2 conforms toSwissprot entry Q13822, with or without the additional C-terminal 6×Histag.

ATX Fermentation:

Recombinant protein was produced by large-scale transient transfectionin 20 L controlled stirred tank bioreactors (Sartorius). During cellgrowth and transfection, temperature, stirrer speed, pH and dissolvedoxygen concentration were maintained at 37° C., 120 rpm, 7.1 and 30% DO,respectively. FreeStyle 293-F cells (Invitrogen) were cultivated insuspension in FreeStyle 293 medium (Invitrogen) and transfected at ca.1-1.5×10E6 cells/mL with above plasmid DNAs using X-tremeGENE Ro-1539(commercial product, Roche Diagnostics) as complexing agent. Cells werefed a concentrated nutrient solution (J Immunol Methods 194 (1996), 19,1-199 (page 193)) and induced by sodium butyrate (2 mM) at 72 hpost-transfection and harvested at 96 h post-transfection. Expressionwas analyzed by Western Blot, enzymatic assay and/or analytical IMACchromatography. After cooling the cell suspension to 4° C. in aflow-through heat exchanger, cell separation and sterile filtration ofsupernatant was performed by filtration through Zeta Plus 60M02 E16(Cuno) and Sartopore 2 XLG (Sartorius) filter units. The supernatant wasstored at 4° C. prior to purification.

ATX Purification:

20 liter of culture supernatant were conditioned for ultrafiltration byadding Brij 35 to a final concentration of 0.02% and by adjusting the pHto 7.0 using 1 M HCl. Then the supernatant was first microfiltredthrough a 0.2 um Ultran-Pilot Open Channel PES filter (Whatman) andafterwards concentrated to 1 liter through an Ultran-Pilot ScreenChannel PES filter with 30 kDa MWCO (Whatman). Prior to IMACchromatography, NiSO₄ was added to a final concentration of 1 mM. Thecleared supernatant was then applied to a HisTrap column (GE Healthcare)previously equilibrated in 50 mM Na₂HPO₄ pH 7.0, 0.5 M NaCl, 10%glycerol, 0.3% CHAPS, 0.02% NaN₃. The column was washed stepwise withthe same buffer containing 20 mM, 40 mM and 50 mM imidazole,respectively. The protein was subsequently eluted using a lineargradient to 0.5 M imidazole in 15 column volumes. ATX containingfractions were pooled and concentrated using an Amicon cell equippedwith a 30 kDa PES filter membrane. The protein was further purified bysize exclusion chromatography on Superdex S-200 prep grade (XK 26/100)(GE Healthcare) in 20 mM BICINE pH 8.5, 0.15 M NaCl, 10% glycerol, 0.3%CHAPS, 0.02% NaN₃. Final yield of protein after purification was 5-10 mgATX per liter of culture supernatant. The protein was stored at −80° C.

Human Atx Enzyme Inhibition Assay

ATX inhibition was measured by a fluorescence quenching assay using aspecifically labeled substrate analogue (MR121 substrate). To obtainthis MR121 substrate, BOC and TBS protected 6-amino-hexanoic acid(R)-3-({2-[3-(2-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-ethoxy)-propionylamino]-ethoxy}-hydroxy-phosphoryloxy)-2-hydroxy-propylester (Ferguson et al., Org Lett 2006, 8 (10), 2023) was labeled withMR121 fluorophore (CAS 185308-24-1,1-(3-carboxypropyl)-11-ethyl-1,2,3,4,8,9,10,11-octahydro-dipyrido[3,2-b:2′,3′-i]phenoxazin-13-ium)on the free amine of the ethanolamine side and then, after deprotection,subsequently with tryptophan on the side of the aminohexanoic acid.

Assay working solutions were made as follows:

Assay buffer (50 mM Tris-HCl, 140 mM NaCl, 5 mM KCl, 1 mM CaCl₂, 1 mMMgCl₂, 0.01% Triton-X-100, pH 8.0;ATX solution: ATX (human His-tagged) stock solution (1.08 mg/mL in 20 mMbicine, pH 8.5, 0.15 M NaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaN₃),diluted to 1.4-2.5× final concentration in assay buffer;MR121 substrate solution: MR121 substrate stock solution (800 μM MR121substrate in DMSO), diluted to 2-5× final concentration in assay buffer.

Test compounds (10 mM stock in DMSO, 8 μL) were obtained in 384 wellsample plates (Corning Costar #3655) and diluted with 8 μL DMSO.Row-wise serial dilutions were made by transferring 8 μL cpd solution tothe next row up to row 0. The compound and control solutions were mixedfive times and 2 μL were transferred to 384 well assay plates (CorningCostar #3702). Then, 15 μL of 41.7 nM ATX solution was added (30 nMfinal concentration), mixed five times and then incubated for 15 minutesat 30° C. 10 μL of MR121 substrate solution was added (1 μM finalconcentration), mixed 30 times and then incubated for 15 minutes at 30°C. Fluorescence was then measured every 2 minutes for 1 hour (PerkinElmer plate: vision multimode reader); light intensity: 2.5%; exp. time:1.4 sec, Filter: Fluo_(—)630/690 nm) and IC₅₀ values were calculatedfrom these readouts.

IC₅₀ values for the examples of this invention are given in the tablebelow:

Example IC50 (μM) 1 1.156 1.01 0.293 1.02 0.444 1.03 0.007 1.04 0.0081.05 0.004 1.06 0.255 1.07 6.108 1.08 1.1995 1.09 0.118 1.10 0.002 1.110.001 1.12 0.44 1.13 0.001 1.14 0.064 1.15 0.0585 1.16 0.001 1.17 0.0251.18 0.013 1.19 0.004 1.20 0.019 1.21 0.118 1.22 0.007 1.23 0.004 1.240.012 1.25 0.002 1.26 0.01 2 0.342 2.01 1.5 3 0.031 4 0.573 5 1.3445 60.6225 7 0.0145 7.01 0.001 7.02 0.003 7.03 0.004 8 0.0085 8.01 0.00758.02 0.014 8.03 0.0055 8.04 0.1665 8.05 0.093 8.06 0.003 8.07 0.001 8.080.0015 8.09 0.001 9A 0.004 9B 0.005

Compounds of formula (I) and their pharmaceutically acceptable salts oresters thereof as described herein have IC₅₀ values between 0.00001 μMand 1000 μM, particular compounds have IC₅₀ values between 0.0005 μM and500 μM, further particular compounds have IC₅₀ values between 0.0005 μMand 50 μM, more particular compounds have IC₅₀ values between 0.0005 μMand 5 μM. These results have been obtained by using the enzymatic assaydescribed above.

The compounds of formula (I) and their pharmaceutically acceptable saltscan be used as medicaments (e.g. in the form of pharmaceuticalpreparations). The pharmaceutical preparations can be administeredinternally, such as orally (e.g. in the form of tablets, coated tablets,dragées, hard and soft gelatin capsules, solutions, emulsions orsuspensions), nasally (e.g. in the form of nasal sprays) or rectally(e.g. in the form of suppositories). However, the administration canalso be effected parenterally, such as intramuscularly or intravenously(e.g. in the form of injection solutions).

The compounds of formula (I) and their pharmaceutically acceptable saltscan be processed with pharmaceutically inert, inorganic or organicadjuvants for the production of tablets, coated tablets, dragées andhard gelatin capsules. Lactose, corn starch or derivatives thereof,talc, stearic acid or its salts etc. can be used, for example, as suchadjuvants for tablets, dragées and hard gelatin capsules.

Suitable adjuvants for soft gelatin capsules, are, for example,vegetable oils, waxes, fats, semi-solid substances and liquid polyols,etc.

Suitable adjuvants for the production of solutions and syrups are, forexample, water, polyols, saccharose, invert sugar, glucose, etc.

Suitable adjuvants for injection solutions are, for example, water,alcohols, polyols, glycerol, vegetable oils, etc.

Suitable adjuvants for suppositories are, for example, natural orhardened oils, waxes, fats, semi-solid or liquid polyols, etc.

Moreover, the pharmaceutical preparations can contain preservatives,solubilizers, viscosity-increasing substances, stabilizers, wettingagents, emulsifiers, sweeteners, colorants, flavorants, salts forvarying the osmotic pressure, buffers, masking agents or antioxidants.They can also contain still other therapeutically valuable substances.

The dosage can vary in wide limits and will, of course, be fitted to theindividual requirements in each particular case. In general, in the caseof oral administration a daily dosage of about 0.1 mg to 20 mg per kgbody weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g.about 300 mg per person), divided preferably into 1-3 individual doses,which can consist, for example, of the same amounts, should it beappropriate. It will, however, be clear that the upper limit givenherein can be exceeded when this is shown to be indicated.

The invention is illustrated hereinafter by Examples, which have nolimiting character.

In case the preparative examples are obtained as a mixture ofenantiomers, the pure enantiomers can be obtained by methods describedherein or by methods known to those skilled in the art, such as e.g.chiral chromatography or crystallization.

EXAMPLES

All examples and intermediates were prepared under nitrogen atmosphereif not specified otherwise.

Abbreviations: aq.=aqueous; CAS-RN=Chemical Abstracts Service RegistryNumber; HPLC=high performance liquid chromatography; MS=mass spectrum;sat.=saturated

Example 1 (3aR,6aS)-3,5-Dichlorobenzyl5-(4-(N-methylsulfamoyl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

To a solution of (3aR,6aS)-3,5-dichlorobenzylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride(intermediate 1; 40 mg, 114 μmol), 4-methylmorpholine (57.5 mg, 569μmol) and 4-(N-methylsulfamoyl)benzoic acid (24.5 mg, 114 μmol) inN,N-dimethylformamide (2 mL) was addedO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate (43.3 mg, 114 μmol) at 0° C., then the reactionmixture was allowed to reach room temperature over 16 h. Afterpartitioning between ethyl acetate and aq. sat. sodium hydrogencarbonate solution the organic layer was washed with water and brine,dried over magnesium sulfate filtered and evaporated. Chromatography(silica gel; ethyl acetate-methanol gradient) afforded the titlecompound (58 mg, 99%). White foam, MS: 512.3 (M+H)⁺.

The following examples were prepared according to example 1, replacing(3aR,6aS)-3,5-dichlorobenzylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride by theappropriate amine and 4-(N-methylsulfamoyl)benzoic acid by theappropriate carboxylic acid.

Amine/Carboxylic Ex. Systematic Name acid MS, m/e 1.01

(3aR,6aS)-3,5- dichlorobenzyl hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1)/5- hydroxypicolinic acid436.2 (M + H)⁺ 1.02

(3aR,6aS)-3,5- dichlorobenzyl hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1)/4- hydroxybenzoic acid 435.2(M + H)⁺ 1.03

(3aS,7aS)-3,5- dichlorobenzyl hexahydro-1H- pyrrolo[3,4-c]pyridine-5(6H)- carboxylate hydrochloride (intermediate 1.1)/4-sulfamoylbenzoic acid 512.5 (M + H)⁺ 1.04

(3aR,6aS)-3,5- dichlorobenzyl hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1)/5- sulfamoylthiophene-2-carboxylic acid 504.3 (M + H)⁺ 1.05

(3aR,6aS)-3,5- dichlorobenzyl hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1)/4- sulfamoylbenzoic acid498.3 (M + H)⁺ 1.06

(3aR,6aS)-3,5- dichlorobenzyl hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1)/4- aminobenzoic acid 434.4(M + H)⁺ 1.07

(3aR,6aS)-3,5- dichlorobenzyl hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1)/5- aminopicolinic acidhydrochloride 435.4 (M + H)⁺ 1.08

(3aR,6aS)-3,5- dichlorobenzyl hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1)/4- cyanobenzoic acid 444.2(M + H)⁺ 1.09

(3aR,6aS)-3,5- dichlorobenzyl hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1)/4- (methoxycarbonyl)- benzoicacid 477.2 (M + H)⁺ 1.10

(E)-1-((3aR,8aS)- octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3- (4-(trifluoromethoxy)phen- yl)prop-2-en-1-one hydrochloride (intermediate2)/4- sulfamoylbenzoic acid 538.5 (M + H)⁺ 1.11

(3aS,6aS)-hexahydro- pyrrolo[3,4-c]pyrrole- 2-carboxylic acid 4-trifluoromethoxy- benzyl ester hydrochloride (intermediate 1.2)/3-fluoro-4-sulfamoyl- benzoic acid (CAS- RN 244606-37-9) 532.5 (M + H)⁺1.12

(3aS,6aS)-hexahydro- pyrrolo[3,4-c]pyrrole- 2-carboxylic acid 4-trifluoromethoxy- benzyl ester hydrochloride (intermediate 1.2)/6-oxo-1,6- dihydropyridine-3- carboxylic acid 452.5 (M + H)⁺ 1.13

(3aS,6aS)-hexahydro- pyrrolo[3,4-c]pyrrole- 2-carboxylic acid 4-trifluoromethoxy- benzyl ester hydrochloride (intermediate 1.2)/5-sulfamoylpicolinic acid (CAS-RN 1308677-67-9) 515.5 (M + H)⁺ 1.14

(3aS,6aS)-hexahydro- pyrrolo[3,4-c]pyrrole- 2-carboxylic acid 4-trifluoromethoxy- benzyl ester hydrochloride (intermediate 1.2)/1-methyl-4-sulfamoyl- 1H-pyrrole-2- carboxylic acid (CAS- RN 878218-38-3)517.5 (M + H)⁺ 1.15

(3aS,6aS)-hexahydro- pyrrolo[3,4-c]pyrrole- 2-carboxylic acid 4-trifluoromethoxy- benzyl ester hydrochloride (intermediate 1.2)/1-methyl-5-sulfamoyl- 1H-pyrrole-2- carboxylic acid (CAS- RN 306936-62-9)517.5 (M + H)⁺ 1.16

(3aS,6aS)-hexahydro- pyrrolo[3,4-c]pyrrole- 2-carboxylic acid 4-trifluoromethoxy- benzyl ester hydrochloride (intermediate 1.2)/6-sulfamoylnicotinic acid (CAS-RN 285135-56-0) 515.6 (M + H)⁺ 1.17

(3aS,6aS)-hexahydro- pyrrolo[3,4-c]pyrrole- 2-carboxylic acid 4-trifluoromethoxy- benzyl ester hydrochloride (intermediate 1.2)/5-hydroxypicolinic acid 452.4 (M + H)⁺ 1.18

(3aS,6aS)-hexahydro- pyrrolo[3,4-c]pyrrole- 2-carboxylic acid 4-trifluoromethoxy- benzyl ester hydrochloride (intermediate 1.2)/4-hydroxybenzoic acid 451.4 (M + H)⁺ 1.19

(3aS,6aS)-hexahydro-pyrrolo[3,4- c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester hydrochloride (intermediate 1.2)/2-fluoro-4-sulfamoylbenzoic acid (CAS-RN 714968-42-0) 530.3 (M − H) 1.20

1-((3aS,6aS)- hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-3-(4-(trifluoromethoxy)phenyl)propan- 1-one dihydrochloride (intermediate2.2)/6- sulfamoylnicotinic acid (CAS-RN 285135-56-0) 513.3 (M + H)⁺ 1.21

(4-ethoxyquinolin-2- yl)((3aS,6aS)- hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone hydrochloride (intermediate 2.1)/6-sulfamoylnicotinic acid (CAS- RN 285135-56-0) 496.2 (M + H)⁺ 1.22

(3aS,6aS)-4-cyano-2- pivalamidobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1.3)/3-fluoro-4-sulfamoylbenzoic acid (CAS-RN 244606-37-9) 570.3 (M − H) 1.23

(3aS,6aS)-4-cyano-2- pivalamidobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1.3)/6- sulfamoylnicotinicacid (CAS-RN 285135-56-0) 553.3 (M − H) 1.24

(3aS,6aS)-4-cyano-2- pivalamidobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1.3)/4- sulfamoylbenzoicacid 552.3 (M − H) 1.25

(3aS,6aS)-4-cyano-2- pivalamidobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1.3)/2-fluoro-4-sulfamoylbenzoic acid (CAS-RN 714968-42-0) 570.4 (M − H) 1.26

(3aS,6aS)-4-cyano-2- pivalamidobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (intermediate 1.3)/5- sulfamoylpicolinicacid (CAS-RN 1308677-67-9) 553.3 (M − H)

Example 2 (3aR,6aS)-3,5-Dichlorobenzyl5-(4-acetamidobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

Acetyl chloride (8.7 mg, 110 μmol) was added at 0° C. to a suspension of(3aR,6aS)-3,5-dichlorobenzyl5-(4-aminobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(example 1.06; 40 mg, 92.1 μmol) and triethylamine (28.0 mg, 276 μmol)in dichloromethane (1 mL). The ice bath was removed, then after 90 minanother portion of acetyl chloride (5.8 mg, 73 μmol) was added, thenafter another 2 h the reaction mixture was partitioned betweendichloromethane and brine. The organic layer was dried over magnesiumsulfate, filtered, and evaporated. Chromatography (silica gel; ethylacetate-methanol gradient) produced the title compound (27 mg, 61%).White foam, MS: 476.4 (M+H)⁺.

Example 2.1 (3aR,6aS)-3,5-Dichlorobenzyl5-(5-acetamidopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

The title compound was produced in analogy to example 2, replacing(3aR,6aS)-3,5-dichlorobenzyl5-(4-aminobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate by(3aR,6aS)-3,5-dichlorobenzyl5-(5-aminopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(example 1.07). White solid, MS: 477.4 (M+H)⁺.

Example 3 (3aR,6aS)-3,5-Dichlorobenzyl5-(4-sulfamoylphenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

To a suspension of (3aR,6aS)-3,5-dichlorobenzylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride(intermediate 1; 50 mg, 142 μmol) and pyridine (112 mg, 1.42 mmol) intetrahydrofuran (1 mL) was added a solution of4-sulfamoylbenzene-1-sulfonyl chloride (32.7 mg, 128 μmol) intetrahydrofuran (1 mL) at 0° C., then the reaction mixture was stirredat room temperature for 16 h. After partitioning between ethyl acetateand sat. aq. sodium hydrogencarbonate solution, the organic layer waswashed with brine, dried over magnesium sulfate, filtered, andevaporated. The residue was triturated in ethyl acetate to produce thetitle compound (45 mg, 59%). Light yellow solid, MS: 532.1 (M−H)⁻.

Example 4 (3aR,6aS)-3,5-Dichlorobenzyl5-(4-(1H-tetrazol-5-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

To a solution of (3aR,6aS)-3,5-dichlorobenzyl5-(4-cyanobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(example 1.08; 83 mg, 187 μmol) in 2-propanol (4 mL) and water (5 mL)was added sodium azide (24.3 mg, 374 μmol) and zinc bromide (21.0 mg,93.4 μmol). The reaction mixture was heated at 80° C. for 16 h, thenanother portion of sodium azide (24.3 mg, 374 μmol) and zinc bromide(21.0 mg, 93.4 μmol) was added, then after another 14 h the reactionmixture was partitioned between ethyl acetate and water. The organiclayer was washed with water and brine, dried over magnesium sulfate,filtered, and evaporated. Chromatography (silica gel; gradientdichloromethane to dichloromethane/methanol 4:1) afforded the titlecompound (46 mg, 51%). White foam, MS: 487.4 (M+H)+.

Example 54-((3aR,6aS)-5-((3,5-Dichlorobenzyloxy)carbonyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzoicacid

To a solution of (3aR,6aS)-3,5-dichlorobenzyl5-(4-(methoxycarbonyl)benzoyl)hexahydro-pyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(example 1.09; 82 mg, 172 μmol) in tetrahydrofuran (1.5 mL) was added 2M aq. sodium hydroxide solution (515 μl, 1.03 mmol). The reactionmixture was stirred at room temperature for 2 h, then heated at 50° C.for 3 h, then partitioned between ethyl acetate and 1 M aq. hydrochloricacid solution. The organic layer was washed with water and brine, driedover magnesium sulfate, filtered, and evaporated to afford the titlecompound (74 mg, 93%). White solid, MS: 463.6 (M−H)⁻.

Example 6 (3aR,6aS)-3,5-Dichlorobenzyl5-(5-(methylsulfonamido)picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

Step 1: (3aR,6aS)-3,5-Dichlorobenzyl5-(5-(N-(methylsulfonyl)methylsulfonamido)-picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

A solution of methanesulfonyl chloride (21 mg, 184 μmol) indichloromethane (0.5 mL) was added dropwise at 0° C. to a solution of(3aR,6aS)-3,5-dichlorobenzyl5-(5-aminopicolinoyl)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(example 1.07; 40 mg, 91.9 μmol) and triethylamine (27.9 mg, 276 μmol)in dichloromethane (1 mL). The ice bath was removed, then after 18 h thereaction mixture was partitioned between dichloromethane and water. Theorganic layer was washed with brine, dried over magnesium sulfate,filtered, and evaporated. Chromatography (silica gel; gradientdichloromethane to dichloromethane/methanol/25% aq. ammonia solution95:5:0.25) produced the title compound (42 mg, 77%). White foam, MS:591.4 (M+H)⁺.

Step 2: (3aR,6aS)-3,5-Dichlorobenzyl5-(5-(methylsulfonamido)picolinoyl)hexahydro-pyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

To a solution of (3aR,6aS)-3,5-dichlorobenzyl5-(5-(N-(methylsulfonyl)methylsulfonamido)-picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(36 mg, 60.9 μmol) in tetrahydrofuran (0.5 mL) was added 1 M aq. sodiumhydroxide solution (122 μl, 122 μmol), then after 1 h the reactionmixture was partitioned between ethyl acetate and sat. aq. ammoniumchloride solution. The organic layer was washed with water and brine,dried over magnesium sulfate, filtered, and evaporated to afford thetitle compound (29 mg, 93%). White foam, MS: 513.4 (M+H)⁺.

Example 7(3aS,6aS)-5-(4-Sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid 3-chloro-5-methanesulfonyl-benzyl ester

To a solution of (3-chloro-5-(methylsulfonyl)phenyl)methanol(intermediate 5; 23.3 mg, 105 μmol) in acetonitrile (4 ml) was addedN,N′-carbonyldiimidazole (18.0 mg, 111 μmol) at room temperature, thenafter 2 h triethylamine (53.4 mg, 527 μmol) and4-((3aR,6aR)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamidehydrochloride (intermediate 4; 35 mg, 105 μmol) were added and thereaction mixture was heated at reflux for 15 h. After cooling thereaction mixture was partitioned between ethyl acetate and sat. aq.ammonium chloride solution. The aqueous layer was back-extracted withethyl acetate, then the combined organic layers were washed with brine,dried over magnesium sulfate, filtered, and evaporated. The residue wastriturated in tert-butyl methyl ether to afford the title compound (26mg, 46%). White solid, MS: 542.5 (M+H)⁺.

The following examples were prepared according to example 7, replacing4-((3aR,6aR)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamidehydrochloride by the appropriate amine and(3-chloro-5-(methylsulfonyl)phenyl)methanol by the appropriate alcohol.

Ex. Systematic Name Amine/Alcohol MS, m/e 7.01

4-((3aR,6aS)- octahydropyrrolo[3,4- c]pyrrole-2-carbonyl)-benzenesulfonamide hydrochloride (intermediate 4.1)/(2-fluoro-4-(trifluoro- methoxy)- phenyl)methanol 532.5 (M + H)⁺ 7.02

4-((3aR,6aS)- octahydropyrrolo[3,4- c]pyrrole-2-carbonyl)-benzenesulfonamide hydrochloride (intermediate 4.1)/(4-(trifluoromethoxy)- phenyl)methanol 514.6 (M + H)⁺ 7.03

4-((3aR,6aR)- octahydropyrrolo[3,4- c]pyrrole-2-carbonyl)-benzenesulfonamide hydrochloride (intermediate 4)/(4-(trifluoromethoxy)- phenyl)methanol 514.5 (M + H)⁺

Example 84-{(3aR,6aR)-5-[3-(4-Trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide

To a white suspension of4-((3aR,6aR)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamidehydrochloride (intermediate 4; 40 mg, 121 μmol), N-methylmorpholine(61.0 mg, 603 μmol) and 3-(4-(trifluoromethoxy)phenyl)propanoic acid(28.2 mg, 121 μmol) in N,N-dimethylformamide (5 ml) was addedO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate (45.8 mg, 121 μmol) at 0° C., and the ice bath wasremoved after 15 min. After 16 h, the reaction mixture was partitionedbetween dichloromethane and sat. aq. sodium hydrogencarbonate solution.The organic layer was washed with sat. aq. ammonium chloride solutionand brine, dried over magnesium sulfate, filtered and evaporated. Aftertrituration in tert-butyl methyl ether the precipitate was collected byfiltration to afford the title compound (44 mg, 71%). White solid, MS:512.5 (M+H)⁺.

The following examples were produced in analogy to example 8, replacing4-((3aR,6aR)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamidehydrochloride by the appropriate amine and3-(4-(trifluoromethoxy)phenyl)propanoic acid by the appropriatecarboxylic acid.

Amine/Carboxylic Ex. Systematic Name acid MS, m/e 8.01

4-((3aR,6aR)- octahydropyrrolo[3,4- c]pyrrole-2-carbonyl)-benzenesulfonamide hydrochloride (intermediate 4)/(E)-3-(4-(trifluoromethoxy)- phenyl)acrylic acid 510.5 (M + H)⁺ 8.02

4-((3aR,6aS)- octahydropyrrolo[3,4- c]pyrrole-2-carbonyl)-benzenesulfonamide hydrochloride (intermediate 4.1)/4-isopropoxy-2-naphthoic acid (CAS-RN 1368865-02-4) 508.4 (M + H)⁺ 8.03

4-((3aR,6aS)- octahydropyrrolo[3,4- c]pyrrole-2-carbonyl)-benzenesulfonamide hydrochloride (intermediate 4.1)/l-(2,2,2-trifluoroethoxy)- isoquinoline-3- carboxylic acid (CAS- RN1096982-79-4) 549.6 (M + H)⁺ 8.04

4-((3aR,6aS)- octahydropyrrolo[3,4- c]pyrrole-2-carbonyl)-benzenesulfonamide hydrochloride (intermediate 4.1)/1-methyl-5-(trifluoro- methoxy)-1H-indole-2- carboxylic acid (CAS- RN1257122-42-1) 537.5 (M + H)⁺ 8.05

4-((3aR,6aS)- octahydropyrrolo[3,4- c]pyrrole-2-carbonyl)-benzenesulfonamide hydrochloride (intermediate 4.1)/4-isopropoxyquinoline-2- carboxylic acid (CAS- RN 1406553-19-2) 509.6 (M +H)⁺ 8.06

4-((3aR,6aS)- octahydropyrrolo[3,4- c]pyrrole-2-carbonyl)-benzenesulfonamide hydrochloride (intermediate 4.1)/4′-chlorobiphenyl-4- carboxylic acid (CAS- RN 5748-41-4) 510.5 (M + H)⁺8.07

4-((3aR,6aS)- octahydropyrrolo[3,4- c]pyrrole-2-carbonyl)-benzenesulfonamide hydrochloride (intermediate 4.1)/3-(2-fluoro-4-(trifluoro- methoxy)phenyl)- propanoic acid (CAS- RN1240257-16-2) 530.3 (M + H)⁺ 8.08

4-((3aR,6aS)- octahydropyrrolo[3,4- c]pyrrole-2-carbonyl)-benzenesulfonamide hydrochloride (intermediate 4.1)/3-(4-(trifluoromethoxy)- phenyl)propanoic acid 512.3 (M + H)⁺ 8.09

4-((3aR,6aR)- octahydropyrrolo[3,4- c]pyrrole-2-carbonyl)-benzenesulfonamide hydrochloride (intermediate 4)/3-(2-fluoro-4-(trifluoro- methoxy)phenyl)- propanoic acid (CAS- RN1240257-16-2) 530.5 (M + H)⁺

Examples 9A and 9B (−)-trans-3,5-Dichlorobenzyl2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylateand (+)-trans-3,5-dichlorobenzyl2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate

The racemate, trans-3,5-dichlorobenzyl2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate(example 1.03; 60 mg, 117 μmol) was separated by preparative HPLC usinga Reprosil Chiral-NR column as the stationary phase and heptane/ethanol3:2 as the mobile phase. This produced the faster eluting (−)-enantiomer(example 9A; 23 mg, 38%; white solid, MS: 512.4 (M+H)), and the slowereluting (+)-enantiomer (example 9B; 22 mg, 36%; orange foam, MS: 512.4(M+H)⁺).

Intermediates Intermediate 1 (3aR,6aS)-3,5-Dichlorobenzylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride Step 1:(3aR,6aS)-2-tert-Butyl5-(3,5-dichlorobenzyl)tetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-dicarboxylate

To a light brown solution of (3,5-dichlorophenyl)methanol (425 mg, 2.35mmol) in dichloromethane (7 mL) was added N,N′-carbonyldiimidazole (401mg, 2.47 mmol). The solution was stirred at room temperature for 3 h,then (3aR,6aS)-tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (CAS-RN 250275-15-1;526 mg, 2.35 mmol) was added, then after 15 h the reaction mixture waspartitioned between 1 M aq. hydrochloric acid solution anddichloromethane. The organic layer was washed with brine, dried overmagnesium sulfate, filtered and evaporated to afford the title compound(972 mg, 99%). Light brown viscous oil, MS: 359.2 (M-C(CH₃)₃+H)⁺.

Step 2: (3aR,6aS)-3,5-Dichlorobenzylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride

To a solution of (3aR,6aS)-2-tert-butyl5-(3,5-dichlorobenzyl)tetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-dicarboxylate(962 mg, 2.32 mmol) in 2-propanol (4 mL) was added hydrochloric acid(5-6 M in 2-propanol) (11.6 mL, 57.9 mmol), then after 3 h the reactionmixture was evaporated. The residue taken up in ethyl acetate and a fewdrops of ethanol, then the precipitate was collected by filtration toproduce the title compound (738 mg, 91%). White solid, MS: 315.3 (M+H)⁺.

The following intermediates were prepared according to intermediate 1,replacing (3aR,6aS)-tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate by the appropriateamine and (3,5-dichlorophenyl)methanol by the appropriate alcohol.

No. Systematic Name Amine Alcohol MS, m/e 1.1 trans-3,5-dichlorobenzyltrans-tert-butyl (3,5- 329.4 (M + H)⁺ hexahydro-1H-pyrrolo[3,4-hexahydro-1H- dichlorophenyl)- c]pyridine-5 pyrrolo[3,4-c]pyridine-methanol (6H)-carboxylate hydrochloride 2(3H)-carboxylate (CAS- RN1251014-37-5) 1.2 (3aS,6aS)-hexahydro- (3aR,6aR)-tert-butyl(4-(trifluoro- 331.5 (M + H)⁺ pyrrolo[3,4-c]pyrrole-2-hexahydropyrrolo[3,4- methoxy)- carboxylic acid 4- c]pyrrole-2(1H)-phenyl)- trifluoromethoxy-benzyl carboxylate methanol esterhydrochloride (intermediate 3.1)

Intermediate 2(E)-1-((3aR,8aS)-Octahydropyrrolo[3,4-d]azepin-6(7H)-yl)-3-(4-(trifluoromethoxy)-phenyl)prop-2-en-1-onehydrochloride Step 1: (3aR,8aS)-tert-butyl6-((E)-3-(4-(trifluoromethoxy)phenyl)acryloyl)octahydro-pyrrolo[3,4-d]azepine-(1H)-carboxylate

To a solution of (3aR,8aS)-tert-butyloctahydropyrrolo[3,4-d]azepine-2(1H)-carboxylate hydrochloride (CAS-RN1251013-07-6; 1.5 g, 5.42 mmol), 4-methylmorpholine (2.19 g, 21.7 mmol)and (E)-3-(4-(trifluoromethoxy)phenyl)acrylic acid (1.26 g, 5.42 mmol)in N,N-dimethylformamide (30 ml) was addedO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate (2.06 g, 5.42 mmol) at 0° C. After 60 min the icebath was removed, then after 16 h the reaction mixture was partitionedbetween ethyl acetate and sat. aq. sodium hydrogencarbonate solution.The organic layer was washed with sat. aq. ammonium chloride solution,water, and brine, dried over magnesium sulfate, filtered, andevaporated. The residue was triturated in heptane/ethyl acetate 9:1 toproduce the title compound (2.20 g, 89%). White solid, MS: 399.5(M-isobutene+H)⁺.

Step 2:(E)-1-((3aR,8aS)-Octahydropyrrolo[3,4-d]azepin-6(7H)-yl)-3-(4-(trifluoromethoxy)-phenyl)prop-2-en-1-onehydrochloride

The title compound was produced in analogy to intermediate 1, step 2from (3aR,8aS)-tert-butyl6-((E)-3-(4-(trifluoromethoxy)phenyl)acryloyl)octahydropyrrolo[3,4-d]azepine-2(1H)-carboxylate.White solid, MS: 355.5 (M+H)⁺.

The following intermediates were prepared according to intermediate 2,replacing (3aR,8aS)-tert-butyloctahydropyrrolo[3,4-d]azepine-2(1H)-carboxylate hydrochloride by theappropriate amine and (E)-3-(4-(trifluoromethoxy)phenyl)acrylic acid bythe appropriate carboxylic acid.

No. Systematic Name Amine Carboxylic acid MS, m/e 2.1(4-ethoxyquinolin-2-yl) (3aR,6aR)-tert-butyl 4-ethoxy- 312.2 (M + H)⁺((3aS,6aS)-hexa- hexahydropyrrolo[3,4- quinoline-2-hydropyrrolo[3,4-c]pyrrol- c]pyrrole-2(1H)- carboxylic acid2(1H)-yl)methanone hydrochloride carboxylate (intermediate 3.1) (CAS-RN40609-78-7) 2.2 1-((3aS,6aS)-hexahydro- (3aR,6aR)-tert-butyl3-(4-(trifluoro- 329.5 (M + H)⁺ pyrrolo[3,4-c]pyrrol-hexahydropyrrolo[3,4- methoxy)- 2(1H)-yl)-3-(4-(trifluoro-c]pyrrole-2(1H)- phenyl)- methoxy)phenyl)propan-1- carboxylate(intermediate 3.1) propanoic acid one dihydrochloride

Intermediate 3 (3aS,6aS)-tert-Butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate Step 1:(3R,4R)-tert-Butyl3,4-bis((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate

To a solution of (3R,4R)-tert-butyl3,4-bis(hydroxymethyl)pyrrolidine-1-carboxylate (CAS-RN 895245-32-6;2.97 g, 12.8 mmol) and N,N-diisopropylethylamine (9.96 g, 77.0 mmol) indichloromethane (70 ml) was added a solution of methanesulfonyl chloride(4.41 g, 38.5 mmol) in dichloromethane (5 ml) dropwise at 0° C., thenafter 1 h the reaction mixture was treated with sat. aq. ammoniumchloride and extracted with ethyl acetate. The organic layer was washedwith sat. aq. sodium hydrogencarbonate solution and brine, dried overmagnesium sulfate, filtered, and evaporated. Chromatography (silica gel;heptane-ethyl acetate gradient) produced the title compound (4.22 g,85%). Light yellow oil, MS: 332.4 (M-isobutene+H)⁺.

Step 2: (3aS,6a5)-tert-Butyl5-benzylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

To a solution of (3R,4R)-tert-butyl3,4-bis((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate (4.22 g,10.9 mmol) in acetonitrile (100 ml) was added potassium carbonate (15.1g, 109 mmol) and phenylmethanamine (3.5 g, 32.7 mmol). The reactionmixture was heated at 95° C. for 45 h, then cooled to room temperatureand partitioned between ethyl acetate and water. The organic layer waswashed with sat. aq. ammonium chloride solution, sat. aq. sodiumhydrogencarbonate solution, and brine, dried over magnesium sulfate,filtered, and evaporated. Chromatography (silica gel; ethylacetate-methanol gradient) produced the title compound (2.23 g 68%).Light yellow solid, MS: 303.5 (M+H)⁺.

Step 3: (3aS,6aS)-tert-Butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

To a solution of (3aS,6a5)-tert-butyl5-benzylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (2.22 g, 7.34mmol, Eq: 1.00) in methanol (20 mL) was added palladium (10% on carbon,220 mg, 7.34 mmol), and the reaction mixture was stirred under ahydrogen atmosphere (1 bar) at room temperature for 24 h, then insolublematerial was removed by filtration through diatomaceous earth. Thefiltrate was concentrated to produce the title compound (1.60 g, 100%).White waxy solid, MS: 213.5 (M+H)⁺.

Intermediate 3.1 (3aR,6aR)-tert-Butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

The title compound was produced in analogy to intermediate 3, replacing(3R,4R)-tert-butyl 3,4-bis(hydroxymethyl)pyrrolidine-1-carboxylate by(3S,4S)-tert-butyl 3,4-bis(hydroxymethyl)pyrrolidine-1-carboxylate(CAS-RN 895245-30-4). White waxy solid, MS: 213.3 (M+H)⁺.

Intermediate 44-((3aR,6aR)-Octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamidehydrochloride Step 1: (3aS,6aS)-tert-Butyl5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

To a solution of (3aS,6a5)-tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (intermediate 3; 206mg, 970 μmol), N-methylmorpholine (294 mg, 2.91 mmol) and4-sulfamoylbenzoic acid (203 mg, 970 μmol) in N,N-dimethylformamide (10ml) was added 047-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate (369 mg, 970 μmol) at 0° C., then after 10 min theice-bath was removed. After 16 h the reaction mixture was partitionedbetween dichloromethane and sat. aq. sodium hydrogencarbonate solution.The organic layer was washed with sat. aq. ammonium chloride solutionand brine, dried over magnesium sulfate, filtered and evaporated. Aftertrituration in tert-butyl methyl ether the precipitate was collected byfiltration to afford the title compound (348 mg, 91%). Light yellowsolid, MS: 396.6 (M+H)⁺.

Step 2:4-((3aR,6aR)-Octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamidehydrochloride (intermediate 4)

The title compound was produced in analogy to intermediate 1, step 2from (3aS,6aS)-tert-butyl5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate.Light yellow solid, MS: 296.5 (M+H)⁺.

Intermediate 5 (3-Chloro-5-(methylsulfonyl)phenyl)methanol

To a solution of 3-chloro-5-(methylsulfonyl)benzoic acid (CAS-RN151104-63-1; 500 mg, 2.13 mmol) in tetrahydrofuran (5 mL) was addedslowly borane-tetrahydrofuran complex solution (1 M solution intetrahydrofuran, 5.33 mL, 5.33 mmol) at 0° C., then after 3 h theice-bath was removed and the rection mixture was stirred at roomtemperature overnight. The reaction mixture was then carefully treatedwith methanol (3 mL) and evaporated. The residue was partitioned betweenethyl acetate and water. The organic layer was washed with brine, driedover magnesium sulfate, filtered, and evaporated. Chromatography (silicagel; heptane-ethyl acetate gradient afforded the title compound (428 mg,91%). White solid, MS: 221.3 (M+H)⁺.

Intermediate 6 N-(5-Cyano-2-(hydroxymethyl)phenyl)pivalamide Step 1:Methyl 4-cyano-2-pivalamidobenzoate

To a solution of methyl 2-amino-4-cyanobenzoate (CAS-RN 159847-83-3; 776mg, 4.4 mmol) in pyridine (6 mL) was added pivaloyl chloride (637 mg,5.29 mmol) dropwise at 0° C., then after 2 h the reaction mixture waspartitioned between 1 M aq. hydrochloric acid solution and ethylacetate/2-methyltetrahydrofuran. The organic layer was washed withwater, 2 M aq. sodium carbonate solution, and brine, dried overmagnesium sulfate, filtered, and evaporated. The residue was trituratedin ethyl acetate to afford the title compound (819 mg). The motherliquor was evaporated and triturated in tert-butyl methyl ether toproduce a second crop of product (148 mg). Combined yield: 967 mg (84%).White solid, MS: 261.1 (M−H)⁻.

N-(5-cyano-2-(hydroxymethyl)phenyl)pivalamide

A suspension of calcium chloride (592 mg, 5.33 mmol) in ethanol (15 mL)was added at room temperature to a solution of methyl4-cyano-2-pivalamidobenzoate (694 mg, 2.67 mmol) in tetrahydrofuran (15mL), then sodium borohydride (403 mg, 10.7 mmol) was added. After 2 hthe reaction mixture was poured upon ice water and sat. ammoniumchloride solution and extracted with ethyl acetate. The organic layerwas washed with brine, dried over magnesium sulfate, filtered, andevaporated. The residue was triturated in tert-butyl methyl ether toproduce the title compound (293 mg). The mother liquour was evaporatedand purified by chromatography (dichloromethane-methanol gradient) toproduce another crop of product (240 mg). Combined yield: 533 mg; (86%).White solid, MS: 231.1 (M−H)⁻.

1. A Compound of formula (I)

wherein R¹ is substituted cycloalkyl, substituted cycloalkylalkyl,substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl,substituted phenylcycloalkyl, substituted phenylalkenyl, substitutedphenylalkynyl, substituted naphthyl, substituted naphthylalkyl,substituted naphthyloxyalkyl, substituted naphthylalkenyl, substitutedpyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl,substituted pyridinylalkynyl, substituted thiophenyl, substitutedthiophenylalkyl, substituted thiophenylalkenyl, substitutedthiophenylalkynyl, substituted indolyl, substituted quinolyl,substituted isoquinolyl, substituted 2,3-dihydro-1H-isoindol-2-yl,substituted 1H-indol-2-yl or substituted benzofuran-2-yl whereinsubstituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl,substituted phenylalkyl, substituted phenoxyalkyl, substitutedphenylcycloalkyl, substituted phenylalkenyl, substituted phenylalkynyl,substituted naphthyl, substituted naphthylalkyl, substitutednaphthyloxyalkyl, substituted naphthylalkenyl, substituted pyridinyl,substituted pyridinylalkyl, substituted pyridinylalkenyl, substitutedpyridinylalkynyl, substituted thiophenyl, substituted thiophenylalkyl,substituted thiophenylalkenyl, substituted thiophenylalkynyl,substituted indolyl, substituted quinolyl, substituted isoquinolyl,substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl andsubstituted benzofuran-2-yl are substituted with R⁷, R⁸ and R⁹; R² issubstituted phenyl, substituted pyridinyl, substituted pyrrolyl,oxodihydropyridinyl or substituted thiophenyl, wherein substitutedphenyl, substituted pyridinyl, substituted pyrrolyl and substitutedthiophenyl are substituted with R¹⁰, R¹¹ and R¹²; Y is —OC(O)—,—NR⁵C(O)—, —C(O)—, —S(O)₂—,

A is —N— or CH—; W is —O—, —S—, —NR⁶—, —C(O)—, —S(O)₂—, or —CR³R⁴—; R³and R⁴ are independently selected from H, halogen, alkyl and cycloalkyl;R⁵ and R⁶ are independently selected from H, alkyl and cycloalkyl; R⁷,R⁸ and R⁹ are independently selected from H, alkyl, hydroxyalkyl,haloalkyl, hydroxyhaloalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkoxy, cycloalkoxy, cycloalkoxyalkyl, cycloalkylalkoxyalkyl,alkoxy, alkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkoxyalkoxy,alkoxyalkoxyalkyl, phenyl, substituted phenyl, pyridinyl, substitutedpyridinyl, halogen, hydroxy, cyano, alkylsulfanyl, haloalkylsulfanyl,cycloalkylsulfanyl, alkylsulfinyl, haloalkylsulfinyl,cycloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,cycloalkylsulfonyl, substituted aminosulfonyl, substituted amino andsubstituted aminoalkyl, wherein substituted aminosulfonyl, substitutedamino and substituted aminoalkyl are substituted on the nitrogen atomwith one to two substituents independently selected from H, alkyl,cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyland cycloalkylcarbonyl, and wherein substituted phenyl and substitutedpyridinyl are optionally substituted with one to three substituentsindependently selected from alkyl, halogen, haloalkyl, alkoxy andhaloalkoxy, wherein at least one of R⁷, R⁸ and R⁹ is not H; R¹⁰ issubstituted aminosulfonyl, alkoxycarbonyl, alkylcarbonylamino,alkylsulfonylamino, substituted amino, carboxy, cyano, hydroxy ortetrazolyl, wherein substituted amino is substituted on the nitrogenatom with one to two substituents independently selected from H, alkyl,cycloalkyl, cycloalkylalkyl, hydroxyalkyl and alkoxyalkyl; R¹¹ and R¹²are independently selected from H, alkyl, cycloalkyl, alkoxy, halogenand haloalkyl; m, n, p and q are independently selected from 1 or 2; orpharmaceutically acceptable salts.
 2. The compound according to claim 1,wherein R¹ is substituted phenyl, substituted phenylalkyl, substitutedphenylalkenyl, substituted naphthyl, substituted indolyl, substitutedquinolyl, or substituted isoquinolyl, wherein substituted phenyl,substituted phenylalkyl, substituted phenylalkenyl, substitutednaphthyl, substituted indolyl, substituted quinolyl and substitutedisoquinolyl are substituted with R⁷, R⁸ and R⁹.
 3. The compoundaccording to claim 1, wherein R¹ is phenylalkyl substituted with R⁷, R⁸and R⁹.
 4. The compound according to claim 1, wherein R¹ is3,5-dichlorobenzyl, 4-trifluoromethoxybenzyl or4-trifluoromethoxyphenylethyl.
 5. The compound according to claim 1,wherein R² is substituted phenyl or substituted pyridinyl, whereinsubstituted phenyl and substituted pyridinyl are substituted with R¹⁰,R¹¹ and R¹².
 6. The compound according to claim 1, wherein R² is phenylsubstituted phenyl with R¹⁰, R¹¹ and R¹².
 7. The compound according toclaim 1, wherein R² is 4-aminosulfonylphenyl,3-fluoro-4-aminosulfonylphenyl, 3-aminosulfonylpyridin-6-yl or2-aminosulfonylpyridin-5-yl.
 8. The compound according to claim 1,wherein Y is —OC(O)— or —C(O)—.
 9. The compound according to claim 1,wherein A is —N—.
 10. The compound according to claim 1, wherein W is—C(O)— or —S(O)₂—.
 11. The compound according to claim 1, wherein W is—C(O)—.
 12. The compound according to claim 1, wherein R⁷, R⁸ and R⁹ areindependently selected from H, alkoxy, haloalkoxy, halogen,alkylsulfonyl and phenyl substituted with one halogen, and wherein atleast one of R⁷, R⁸ and R⁹ is not H.
 13. The compound according to claim1, wherein R⁷ is alkoxy, haloalkoxy, halogen or phenyl substituted withone halogen.
 14. The compound according to claim 1, wherein R⁷ ishaloalkoxy or halogen.
 15. The compound according to claim 1, wherein R⁸is H, halogen or alkylsulfonyl.
 16. The compound according to claim 1,wherein R⁸ is H or halogen.
 17. The compound according to claim 1,wherein R⁹ is H.
 18. The compound according to claim 1, wherein R¹⁰ isaminosulfonyl.
 19. The compound according to claim 1, wherein R¹¹ andR¹² are independently selected from H, alkyl and halogen.
 20. Thecompound according to claim 1, wherein R¹¹ and R¹² are independentlyselected from H and halogen.
 21. The compound according to claim 1,wherein m and n are
 1. 22. The compound according to claim 1, wherein m,n, p and q are
 1. 23. The compound according to claim 1 of formula (Ia).


24. The compound according to claim 1, selected from(3aR,6aS)-3,5-dichlorobenzyl5-(4-(N-methylsulfamoyl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;(3aR,6aS)-3,5-dichlorobenzyl5-(5-hydroxypicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;(3aR,6aS)-3,5-dichlorobenzyl5-(4-hydroxybenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;trans-3,5-dichlorobenzyl2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate; (3aR,6aS)-3,5-dichlorobenzyl5-(5-sulfamoylthiophene-2-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;(3aR,6aS)-3,5-dichlorobenzyl5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;(3aR,6aS)-3,5-dichlorobenzyl5-(4-aminobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;(3aR,6aS)-3,5-dichlorobenzyl5-(5-aminopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;(3aR,6aS)-3,5-dichlorobenzyl5-(4-cyanobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;(3aR,6aS)-3,5-dichlorobenzyl5-(4-(methoxycarbonyl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;4-{(3aS,8aR)-6-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-octahydro-pyrrolo[3,4-d]azepine-2-carbonyl}-benzenesulfonamide;(3aS,6aS)-5-(3-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid 4-trifluoromethoxy-benzyl ester;(3aS,6aS)-5-(6-oxo-1,6-dihydro-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid 4-trifluoromethoxy-benzyl ester;(3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid 4-trifluoromethoxy-benzyl ester;(3aS,6aS)-5-(1-methyl-4-sulfamoyl-1H-pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid 4-trifluoromethoxy-benzyl ester;(3aS,6aS)-5-(1-methyl-5-sulfamoyl-1H-pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid 4-trifluoromethoxy-benzyl ester;(3aS,6aS)-5-(6-sulfamoyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid 4-trifluoromethoxy-benzyl ester;(3aS,6aS)-5-(5-hydroxy-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid 4-trifluoromethoxy-benzyl ester;(3aS,6aS)-5-(4-hydroxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid 4-trifluoromethoxy-benzyl ester; (3aR,6aS)-3,5-dichlorobenzyl5-(4-acetamidobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;(3aR,6aS)-3,5-dichlorobenzyl5-(5-acetamidopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;(3aR,6aS)-3,5-dichlorobenzyl5-(4-sulfamoylphenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;(3aR,6aS)-3,5-dichlorobenzyl5-(4-(1H-tetrazol-5-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;4-((3aR,6aS)-5-((3,5-dichlorobenzyloxy)carbonyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzoicacid; (3aR,6aS)-3,5-dichlorobenzyl5-(5-(methylsulfonamido)picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;(3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid 3-chloro-5-methanesulfonyl-benzyl ester;(3aR,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid 2-fluoro-4-trifluoromethoxy-benzyl ester;(3aR,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid 4-trifluoromethoxy-benzyl ester;(3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid 4-trifluoromethoxy-benzyl ester; 4-{(3aR,6aR)-5-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;4-{(3aR,6aR)-5-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;4-[(3aR,6aS)-5-(4-isopropoxy-naphthalene-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;4-{(3aR,6aS)-5-[1-(2,2,2-trifluoro-ethoxy)-isoquinoline-3-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;4-[(3aR,6aS)-5-(1-Methyl-5-trifluoromethoxy-1H-indole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;4-[(3aR,6aS)-5-(4-Isopropoxy-quinoline-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;4-[(3aS,6aR)-5-(4′-chloro-biphenyl-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;4-{(3aS,6aR)-5-[3-(2-fluoro-4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;4-{(3aS,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;4-((3aR,6aR)-5-(3-(2-fluoro-4-(trifluoromethoxy)phenyl)propanoyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide;(+)-trans-3,5-dichlorobenzyl2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate; (−)-trans-3,5-dichlorobenzyl2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate;(3aS,6aS)-5-(2-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid 4-trifluoromethoxy-benzyl ester;5-{(3aR,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-pyridine-2-sulfonicacid amide;5-((3aS,6aS)-5-(4-ethoxyquinoline-2-carbonyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)pyridine-2-sulfonamide;(3aS,6aS)-5-(3-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester;(3aS,6aS)-5-(6-sulfamoyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester;(3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzylester;(3aS,6aS)-5-(2-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester;(3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester; andpharmaceutically acceptable salts thereof.
 25. A compound according toclaim 1, selected from (3aR,6aS)-3,5-dichlorobenzyl5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;(3aS,6aS)-5-(3-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid 4-trifluoromethoxy-benzyl ester;(3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid 4-trifluoromethoxy-benzyl ester;(3aS,6aS)-5-(6-sulfamoyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid 4-trifluoromethoxy-benzyl ester;(3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid 4-trifluoromethoxy-benzyl ester;4-{(3aR,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;(3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester; andpharmaceutically acceptable salts thereof.
 26. A process to prepare acompound according to claim 1 comprising the reaction of a compound offormula (II) in the presence of a compound of formula (III), wherein R¹,R², A, W, m, n, p and q are as defined above, Y is —OC(O)—.


27. (canceled)
 28. A pharmaceutical composition comprising a compoundaccording to claim 1 and a therapeutically inert carrier. 29-31.(canceled)
 32. A method for the treatment or prophylaxis a renalcondition selected from the group consisting of renal conditions, liverconditions, inflammatory conditions, conditions of the nervous system,fibrotic diseases and acute and chronic organ transplant rejection,which method comprises administering an effective amount of a compoundaccording to claim
 1. 33-34. (canceled)